Process for the preparation of gamma amino acids and intermediates used in said process

ABSTRACT

The invention relates to the preparation of gamma amino acids of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof, and to intermediates used for their preparation. (formula I) wherein R 1  is selected from an alkyl group, an alkenyl group, an alkynyl group and a cycloalkyl group, each of which may be optionally substituted and * denotes a chiral centre. In particular, the present invention provides an efficient synthesis of (S)-pregabalin which is suitable for carrying out on an industrial scale.

TECHNICAL FIELD

The present invention relates to the preparation of gamma amino acids,and pharmaceutically acceptable salts, solvates and prodrugs thereof.

In particular, the invention relates to an preparation of both (S)- and(R)-enantiomers of gamma amino acids. In particular, the inventionrelates to the preparation of (S)-pregabalin and pharmaceuticallyacceptable salts, solvates and prodrugs thereof. The invention furtherrelates to intermediates used in said preparations, processes for theirsynthesis and use thereof to prepare gamma amino acids.

BACKGROUND

(S)-pregabalin is an anticonvulsive drug which is also indicated in thetreatment of generalised anxiety disorder (GAD) in adults, and thetreatment of peripheral and central neuropathic pain in adults. Itschemical name is (3S)-3-(aminomethyl)-5-methylhexanoic acid or(S)-(+)-4-amino-3-(2-methylpropyl)butanoic acid, and it has thefollowing chemical structure:

A synthesis of (S)-pregabalin is described by Hayashi et al. (OrganicLetters, 2007, Vol. 9, No. 25, 5307-5309). The synthesis comprisesconjugate addition of nitromethane to α,β-unsaturated aldehydes in thepresence of a diphenylprolinol silyl ether catalyst to give an aliphaticnitro compound which undergoes oxidation followed by reduction to(S)-pregabalin (Scheme 1).

The catalyst is prepared in six steps. The scale up of the synthesis isdifficult making it unsuitable for use on an industrial scale.

The present invention provides an efficient method for preparing gammaamino acids such as (S)-pregabalin, preferably in high enantiomericpurity.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a process for the preparation ofa compound of formula (I), and pharmaceutically acceptable salts,solvates and prodrugs thereof:

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;which process comprises the step of reacting a compound of formula (IV)with nitromethane in the presence of a catalyst to provide a compound offormula (V);

wherein:R¹ and * are as defined above in relation to the compound of formula(I); R² is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

A further aspect of the invention relates to a process for thepreparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;which process comprises the step of preparing a compound of formula (IV)by reacting a compound of formula (III) with a compound of formula (II):

wherein:R¹ is defined above in relation to the compound of formula (I); R² is analkyl group or aryl group, each of which may be optionally substituted;and X is an electron withdrawing group.

A further aspect of the invention relates to a compound of formula (V),and salts, thereof,

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; R²is an alkyl group or an aryl group, each of which may be optionallysubstituted; * denotes a chiral centre; andX is an electron withdrawing group.

A further aspect of the invention relates to a process for thepreparation of a compound of formula (V), and salts thereof, whichprocess comprises reacting a compound of formula (IV), with nitromethanein the presence of a catalyst:

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; *denotes a chiral centre; R² is an alkyl group or aryl group, each ofwhich may be optionally substituted; and X is an electron withdrawinggroup.

A further aspect of the invention relates to the use of a compound offormula (V):

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; *denotes a chiral centre; R² is an alkyl group or aryl group, each ofwhich may be optionally substituted; and X is an electron withdrawinggroup for the preparation of a compound of formula (I), in particular(S)-pregabalin.

A further aspect of the invention relates to a compound of formula (IV),or salt, thereof,

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; R²is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

A further aspect of the invention relates to a process for thepreparation of a compound of formula (IV), and salts thereof, whichprocess comprises reacting a compound of formula (III) with a compoundof formula (II):

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; R²is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

A further aspect of the invention relates to the use of compound (IV):

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; R²is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group for the preparationof a compound of formula (I), in particular (S)-pregabalin.

A further aspect of the invention relates to a process for thepreparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof:

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;which process comprises preparing a compound of formula (IV) by reactinga compound of formula (IIIA) with a compound of formula (II) to form acompound of formula (IIIB):

wherein:L is a hydroxyl activating group, R¹ is defined above in relation to thecompound of formula (I); and R² is an alkyl group or aryl group, each ofwhich may be optionally substituted; and converting the compound offormula (IIIB) to a compound of formula (IIIC):

wherein:X is an electron withdrawing group; and converting the compound offormula (IIIC) to a compound of formula (IV).

A further aspect of the invention relates to a process for thepreparation of a compound of formula (IV), and salts thereof, whichprocess comprises reacting a compound of formula (IIIA) with a compoundof formula (II) to form a compound of formula (IIIB):

wherein:L is a hydroxyl activating group, R¹ is defined above in relation to thecompound of formula (I);and R² is an alkyl group or aryl group, each of which may be optionallysubstituted; andconverting the compound of formula (IIIB) to a compound of formula(IIIC):

wherein:X is an electron withdrawing group; and converting the compound offormula (IIIC) to a compound of formula (IV).

A further aspect of the present invention relates to a process for thepreparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof:

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;which process comprises the step of reacting a compound of formula (IIA)with a compound of formula (III) in the presence of a catalyst toprovide a compound of formula (V);

wherein:R¹ and * are as defined above in relation to the compound of formula(I); R² is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

A further aspect of the present invention relates to a process for thepreparation of a compound of formula (V), and salts thereof, whichprocess comprises reacting a compound of formula (IIA) with a compoundof formula (III) in the presence of a catalyst;

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted; R²is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

A further aspect relates to the compounds of formula (IIA), (IIIA),(IIIB) and (IIIC) as defined herein above and their use in thepreparation of a compound of formula (I), in particular (S)-pregabalin.

A further aspect of the invention relates to the following compounds andtheir use as catalysts in chemical processes:

wherein Y⁻ is a counterion. Examples of suitable counterions includefluoride, chloride, bromide and iodide. Preferably the counterion isbromide.

DETAILED DESCRIPTION

The present invention provides an efficient four step process for thepreparation of gamma amino acids beginning from readily availablestarting materials (Schemes 2 and 3).

wherein R¹, R² and X are as defined above.

wherein R¹, R² and X are as defined above; with the proviso that X isnot NO₂.

Surprisingly, aqueous solvent has been demonstrated to be suitable forthe reaction of compounds of formula (II) with compounds of formula(III). The ability to use solvents comprising water as a reactionsolvent is preferable on an industrial scale as it is reduces cost andreduces the need to handle harmful solvents. This is advantageous interms of safety and is beneficial for the environment.

The chiral centre is introduced by addition of nitromethane to compoundsof formula (IV) in the presence of a catalyst. This reaction may proceedin high yield and, if a chiral catalyst is used, may proceed with highenantioselectivity. Preferably the reaction does not requirestoichiometric quantities of catalyst.

Preferably, the catalysts employed are cheap and commercially available,or can be easily synthesized.

Preferably the process for the preparation of gamma amino acids of thepresent invention does not require chromatographic purification of theintermediates. This is preferable for a synthesis which may be carriedout on an industrial scale.

GENERAL DEFINITIONS

As used herein, the term “alkyl” includes both saturated straight chainand branched alkyl groups which may be substituted (mono- or poly-) orunsubstituted. Preferably, the alkyl group is a C₁₋₂₀ alkylgroup, morepreferably a C₁₋₁₅, more preferably still a C₁₋₁₀alkyl group, morepreferably still a C₁₋₈ alkyl group, more preferably still a C₁₋₆ alkylgroup. Particularly preferred alkyl groups include, for example, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cert-butyl,n-pentyl, n-hexyl, n-heptyl and n-octyl.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl groupwhich may be substituted (mono- or poly-) or unsubstituted.

As used herein, the term “alkenyl” refers to a carbon chain containingone or more carbon-carbon double bonds, which may be branched orunbranched, and substituted (mono- or poly-) or unsubstituted.Preferably the alkenyl group is a C₂₋₂₀ alkenyl group, more preferably aC₂₋₁₅ alkenyl group, more preferably still a C₂₋₁₀ alkenyl group, morepreferably still a C₂₋₅ alkenyl group, or more preferably still a C₂₋₆alkenyl group.

As used herein, the term “alkynyl” refers to a carbon chain containingone or more carbon-carbon triple bonds, which may be branched orunbranched, and substituted (mono- or poly-) or unsubstituted.Preferably the alkynyl group is a C₂₋₂₀ alkynyl group, more preferably aC₂₋₁₅ alkynyl group, more preferably still a C₂₋₁₀ alkynyl group, morepreferably still a C₂₋₈ alkynyl group, or more preferably still a C₂₋₆alkynyl group.

As used herein, the term “aryl” refers to a C₆₋₁₈aromatic group whichmay be substituted (mono- or poly-) or unsubstituted. Preferably thearyl group is a C₆₋₁₄ aryl group, more preferably a C₆₋₁₀ aryl group.Typical examples include phenyl, naphthyl and anthracenyl.

The term “heteroaryl” refers to an aryl group as defined above whichcontains one or more heteroatoms. Suitable heteroatoms will be apparentto those skilled in the art and include, for example, sulphur, nitrogen,oxygen, phosphorus and silicon.

The term “alkoxy” refers to an O-alkyl group, wherein alkyl is asdefined above. Preferably, the alkoxy group is a C₁₋₂₀ alkoxy group,more preferably a C₁₋₁₅ alkoxy group, more preferably still a C₁₋₁₀alkoxy group, more preferably still a C₁₋₈ alkoxy group, more preferablystill a C₁₋₆ alkoxy group. Particularly preferred alkoxy groups include,for example, methoxy, ethoxy, iso-propoxy, propoxy, butoxy, iso-butoxy,pentoxy and hexoxy.

The term “electron withdrawing group” refers to any group capable ofwithdrawing electrons away from a reaction centre. These groups may beelectron withdrawing either by the inductive effect or the mesomericeffect. In one embodiment the electron withdrawing group is electronwithdrawing via the inductive effect. In another embodiment the electronwithdrawing group is electron withdrawing via the mesomeric effect.Examples of suitable electron withdrawing groups include halogens,nitriles, nitro groups, esters and sulfones. Preferably the electronwithdrawing group is selected from halogens, NO₂, CN, COOR³ and SO₂R³;wherein each R³ group is independently H or an optionally substitutedalkyl group. More preferably the electron withdrawing group is selectedfrom NO₂, CN, COOR³ and SO₂R³; wherein each R³ group is independently Hor an optionally substituted alkyl group. More preferably, X is CN orNO₂. More preferably, X is NO₂.

As used herein the term “hydroxyl activating group” refers to an alkylsulfonyl or aryl sulfonyl compound. Suitable hydroxyl activating groupsinclude compounds of formula R″—SO₂ where R″ is an alkyl group or anaryl group. Suitable alkyl groups include C₁₋₆ alkyl optionallysubstituted with one or more, preferably 1-3, halogen atoms. Preferablythe halogen is fluoro. Suitable aryl groups include phenyl optionallysubstituted with one or more, preferably 1-3, C₁₋₃ alkyl groups.Preferred alkyl and aryl sulfonyl compounds include methanesulfonyl,benzene sulfonyl, p-toluenesulfonyl and trifluoromethanesulfonyl.

Where a term defined above is described as substituted, examples ofsuitable substituents may include one or more of hydroxy, alkyl, aryl,halo, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, nitro andcycloalkyl.

It will be appreciated by those skilled in the art that the compounds offormula (I), (V), (VI) and (VIb) contain a chiral centre (denoted as *)and thus exist in the form a pair of optical isomers (i.e. enantiomers).Thus the compounds of formula (I), (V), (VI) and (VIb) may be either(S)-enantiomers or (R)-enantiomers or mixtures thereof including racemicmixtures.

Salts

The present invention relates to the preparation of all salts of thecompounds described herein. The term “compound” is intended to includeall such salts unless the context requires otherwise.

Acceptable salts of the compounds prepared herein include suitable acidaddition or base salts thereof. A review of suitable pharmaceuticalsalts may be found in Berge et al., J. Pharm. Sci., 66, 1, 19 (1977).Salts are formed, for example with strong inorganic acids such asmineral acids, e.g. sulphuric acid, phosphoric acid or hydrohalic acids;with strong organic carboxylic acids, such as alkanecarboxylic acids of1 to 4 carbon atoms which are unsubstituted or substituted (e.g., byhalogen), such as acetic acid; with saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, forexample ascorbic, glycolic, lactic, malic, tartaric or citric acid; withaminoacids, for example aspartic or glutamic acid; with benzoic acid; orwith organic sulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonicacids which are unsubstituted or substituted (for example, by a halogen)such as methane- or p-toluene sulfonic acid. Salts which are notpharmaceutically acceptable may still be valuable as intermediates.

Solvates

The present invention also includes the preparation of solvate forms,hydrated forms and anhydrous forms of the compounds of formula (I). Theterm “compound” is intended to include all such solvates unless thecontext requires otherwise.

Polymorphs

The invention furthermore encompasses the preparation of the compoundsof formula (I) in their various polymorphic forms. It is wellestablished within the pharmaceutical industry that chemical compoundsmay be isolated in any of such forms by slightly varying the method ofpurification and/or isolation from the solvents used in the syntheticpreparation of such compounds. The term “compound” is intended toinclude all such polymorphs unless the context requires otherwise.

Prodrugs

The invention further includes the preparation of the compounds offormula (I) in prodrug form. Such prodrugs are generally compounds offormula (I) wherein one or more appropriate groups have been modifiedsuch that the modification may be reversed upon administration to ahuman or mammalian subject. Such reversion is usually performed by anenzyme naturally present in such subject, though it is possible for asecond agent to be administered together with such a prodrug in order toperform the reversion in vivo. Examples of such modifications includeesterification wherein the reversion may be carried out be an esteraseetc. Other such systems will be well known to those skilled in the art.The term “compound” is intended to include all such prodrugs unless thecontext requires otherwise.

The Compounds of Formulae (I), (II), (IIA), (III), (IIIA), (IIIB),(IIIC), (IV), (V), (VI) and (VIb)

Throughout the specification, definitions of the substituents R¹, R² andX apply to each of compounds formulae (I), (II), (IIA), (III), (IIIA),(IIIB), (IIIC), (IV), (V), (VI) and (VIb) unless the context requiresotherwise.

Throughout the specification, where substituents R¹, R² and R³ aredefined as optionally substituted, examples of suitable substituents mayinclude one or more of hydroxy, alkyl, aryl, halo, alkoxy, haloalkyl,haloalkoxy, amino, aminoalkyl and cycloalkyl. Preferably, suitablesubstitutents are selected from one or more of hydroxy, alkyl, alkoxy,halo, haloalkoxy and aryl. More preferably, suitable substitutents areselected from one or more of hydroxy, methyl, ethyl, methoxy, ethoxy,halo, CF₃ and phenyl.

In one embodiment X is an electron withdrawing group. In anotherembodiment X is an electron withdrawing group selected from halogens,nitriles, nitro groups, esters and sulfones. In another embodiment X isan electron withdrawing group selected from halogens, NO₂, CN, COOR³ andSO₂R³; wherein each R³ group is independently H or an optionallysubstituted alkyl.

In another embodiment X is an electron withdrawing group selected fromNO₂, CN, COOR³ and SO₂R³; wherein each R³ group is independently H or anoptionally substituted alkyl. Preferably, X is CN or NO₂. Morepreferably, X is NO₂.

In one embodiment R¹ is selected from an alkyl group, an alkenyl group,an alkynyl group and a cycloalkyl group, each of which may be optionallysubstituted.

In one embodiment R² is selected from an alkyl group and a phenyl group,each of which may be optionally substituted.

Preferably, R¹ is an alkyl group, an alkynyl group or a cycloalkyl, eachof which may be optionally substituted. More preferably R¹ is anoptionally substituted alkyl group.

Preferably, R¹ and R² are independently selected C₁₋₂₀ alkyl groups,more preferably a C₁₋₁₅ alkyl groups, more preferably still a C₁₋₁₀alkyl groups, more preferably still a C₁₋₈ alkyl groups, more preferablystill a C₁₋₆ alkyl groups; which may optionally be substituted.

In one embodiment R¹ and R² are independently selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, n-hexyl, n-heptyl and n-octyl.

In one embodiment R¹ and R² are independently selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl.

In one embodiment R¹ is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl and n-octyl; and R² is methyl.

In one embodiment R¹ is selected from methyl, ethyl, n-propyl, n-butyl,iso-butyl, n-heptyl and n-octyl; and R² is methyl.

In a particularly preferred embodiment R¹ is iso-butyl and R² is methyl.

In a most preferred embodiment is R¹ iso-butyl, R² is methyl and X isNO₂.

The Catalyst

In one embodiment, the preparation of the compound of formula (V) iscarried out in the presence of a catalyst.

In one embodiment the catalyst is a phase transfer catalyst. Examples ofphase transfer catalysts include tetraalkylammonium salts such astetrabutylammonium bromide and tetraethylammonium bromide;tetraarylammonium halides; arylalkylammonium halides such astriphenylbutylammonium bromide; trialkylarylphoshonium halides such astrimethylphenylphosphomium bromide; tetraalkylphosphonium halides suchas tetrabutylphosphonium bromide; guanidinium salts; metal salencomplexes; and crown ethers.

In one embodiment the catalyst is an organic amine for example acompound of formula N(Rz)₃, where Rz is independently selected fromhydrogen and C₁₋₆ alkyl. Preferably, one and more preferably two andmore preferably three of Rz are C₁₋₆ alkyl. Most preferably the amine istriethyl amine.

In one embodiment the catalyst is a chiral catalyst.

In one embodiment the chiral catalyst is a cinchona alkaloid derivative.

In one embodiment the cinchona alkaloid derivatives may include, but arenot limited to, compounds of formula (VIIa) or (VIIb):

wherein, M is selected from H, hydroxy, alkoxy, O-alkenyl,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl, amino,NR¹¹C(═O)R¹², C(═O)NR¹³R¹⁴, C(═O)R¹², O(C═O)R¹², C(═O)OR¹², NR¹¹SO₂R¹²,and R⁷; in which each aryl, heteroaryl and cycloalkyl groups may beoptionally substituted.

Preferably M is selected from H, hydroxy, alkoxy, O-alkenyl,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷,more preferably M is selected from H, hydroxy, alkoxy, O-alkenyl and R⁷.Most preferably, M is selected from H, hydroxy and methoxy.

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl, amino, NR¹¹C(═O)R¹²,C(═O)NR¹³R¹⁴, C(═O)R¹², O(C═O)R¹², C(═O)OR¹², NR¹¹SO₂R¹², and R⁷; inwhich each aryl, heteroaryl and cycloalkyl groups may be optionallysubstituted.

Preferably R⁴ is selected from hydroxy, alkoxy, O-alkenyl, optionallysubstituted O(CH₂)_(n)-aryl, amino, NR¹¹SO₂R¹², and R⁷. More preferably,R⁴ is selected from hydroxyl, alkoxy, O-alkenyl, R⁷ and O(CH₂)_(n)-aryloptionally substituted with one or more of halo, NO₂, Me, CF₃ and OMe.Most preferably, R⁴ is selected from hydroxy, O-benzyl,O-bis(trifluoromethyl)benzyl, O-2-nitro-4,5-dimethoxybenzyl and R⁷.

R¹¹, R¹², R¹³ and R¹⁴ are independently selected from H, an alkyl group,an alkenyl group, an alkynyl group, an aryl group, a heteroaryl groupand a cycloalkyl group, each of which may be optionally substituted; orR¹³ and R¹⁴ may together define an optionally substituted C₃-C₂₀cycloalkyl group or C₅-C₁₅ heteroaryl group.

Preferably R¹¹ is selected from H and an alkyl group. More preferably,R¹¹ is selected from H, methyl and ethyl.

Preferably R¹², R¹³ and R¹⁴ are independently selected from H, andoptionally substituted alkyl groups, aryl groups, heteroaryl groups andcycloalkyl groups. More preferably, R¹², R¹³ and R¹⁴ are independentlyselected from H, alkyl, aryl and cycloalkyl.

In one embodiment R¹³ and R¹⁴ together define a piperidinyl, piperazinylor a pyridyl group.

R⁵ and R^(5a) are independently selected from H, alkyl and alkenyl, eachof which may be optionally substituted.

Preferably R⁵ and R^(5a) are independently selected from H, methyl,ethyl, propyl, ethenyl, propenyl. Most preferably R⁵ and R^(5a) areindependently selected from H, ethyl and ethenyl.

R⁶ is selected from an alkyl group, an alkenyl group, an alkynyl group,an aryl group, a heteroaryl group, a cycloalkyl group, a (CH₂)_(n)-arylgroup, a (CH₂)_(n)-heteroaryl group and a (CH₂)_(n)-cycloalkyl group;each of which may be optionally substituted.

Preferably R⁶ is selected from optionally substituted (CH₂)_(n)-arylgroups, (CH₂)_(n)—heteroaryl groups and (CH₂)_(n)-cycloalkyl groups.More preferably R⁶ is an optionally substituted (CH₂)_(n)-aryl group.More preferably, R⁶ is a (CH₂)_(n)-aryl group optionally substitutedwith one or more of halo, alkyl, NO₂, Me, CF₃ and OMe. More preferably,R⁶ is a (CH₂)_(n)-aryl group optionally substituted with one or more ofbromo, tert-butyl, Me and CF₃. More preferably, R⁶ is a (CH₂)_(n)-arylgroup optionally substituted with one or more of halo, NO₂, Me, CF₃ andOMe. More preferably, R⁶ is a (CH₂)_(n)-aryl group optionallysubstituted with one or more of NO₂ and OMe. More preferably R⁶ isselected from 3,5-bis(trifluoromethyl)benzyl, benzyl,2-nitro-4,5-dimethoxybenzyl, 3,5-di-tert-butyl-benzyl,3,5-di-bromo-benzyl, 3,5-di-methyl-benzyl and 9-methylanthracene. Morepreferably R⁶ is selected from 3,5-bis(trifluoromethyl)benzyl,3,5-di-tert-butyl-benzyl, 3,5-di-bromo-benzyl and 3,5-di-methyl-benzyl.Most preferably R⁶ is selected from 3,5-bis(trifluoromethyl)benzyl,benzyl, 2-nitro-4,5-dimethoxybenzyl and 9-methylanthracene.

n=0 to 6. Preferably n=0 to 3, more preferably n=1.

R⁷ is

wherein Q is O or S; and R⁸, R⁹ and R¹⁰ are independently selected fromH, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, aheteroaryl group and a cycloalkyl group, each of which may be optionallysubstituted, or R⁸ and R⁹ may together define an optionally substitutedC₃-C₂₀ cycloalkyl group or an optionally substituted C₅-C₁₅ heteroarylgroup.

Preferably R⁸ is selected from an alkyl group, an aryl group, aheteroaryl group and a cycloalkyl group each of which may be optionallysubstituted. More preferably, R⁸ is selected from alkyl group, an arylgroup and a cycloalkyl group; each of which may be optionallysubstituted. Most preferably, R⁸ is selected from3,5-bis(trifluoromethyl)phenyl, 2-nitro-4,5-dimethoxyphenyl, phenyl andcyclohexane.

Preferably R⁹ and R¹⁰ are independently selected from H and an alkylgroup. More preferably, R⁹ and R¹⁰ are independently selected from H,methyl and ethyl.

In one embodiment R⁸ and R⁹ define an optionally substituted C₃-C₂₀cycloalkyl group or C₅-C₁₅ heteroaryl group.

Preferably R⁸ and R⁹ define an optionally substituted, piperidinyl,piperazinyl or pyridyl group.

Y⁻ is a counterion. Examples of suitable counterions may includefluoride, chloride, bromide and iodide.

In one embodiment the cinchona alkaloid derivatives are dimeric speciesof formula (VIIc) or (VIId) in which R¹⁵ represents a linking groupbetween two compounds of formula VIIIa or VIIb respectively:

wherein M, R⁵, R^(5a) are as defined above and R¹⁵ is selected fromO(CH₂)_(n)-aryl-(CH₂)_(n)O, O(CH₂)_(n)-heteroaryl-(CH₂)_(n)O; each ofwhich may be optionally substituted. Preferably R¹⁵ is selected from thefollowing:

In one preferred embodiment, the catalyst is a compound of formula(VIIa) wherein M is selected from H, hydroxy, alkoxy, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, propyl,ethenyl, propenyl;R⁸ is selected from an alkyl group, an aryl group and a cycloalkyl groupeach of which may be optionally substituted by one or more of halo, CF₃,Me and OMe;R⁹, R¹⁰, R¹¹ are independently selected from H and alkyl; andR¹² is selected from H and alkyl, aryl, cycloalkyl; each of which may beoptionally substituted by one or more of halo, CF₃, Me and OMe.

In another preferred embodiment the catalyst is a compound of formula(VIIa) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹² and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl group, an aryl groupand a cycloalkyl group;In another preferred embodiment the catalyst is a compound of formula(VIIa) wherein M is selected from H, hydroxy, methoxy and R⁷;R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment, the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, alkoxy, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷.

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, propyl,ethenyl, propenyl;R⁶ is selected from (CH₂)_(n)-aryl groups, (CH₂)_(n)-heteroaryl groupsand (CH₂)_(n)-cycloalkyl groups, each of which may optionally besubstituted with one or more halo, NO₂, CF₃, Me and OMe groups;R⁸ is selected from an alkyl group, an aryl group and a cycloalkyl groupeach of which may be optionally substituted by one or more of halo, CF₃,Me and OMe;R⁹, R¹⁰, R¹¹ are independently selected from H and alkyl; andR¹² is selected from H, alkyl, aryl and cycloalkyl; each of which may beoptionally substituted by one or more of halo, CF₃, Me and OMe.

In another preferred embodiment, the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, alkoxy, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, propyl,ethenyl, propenyl;R⁶ is selected from (CH₂)_(n)-aryl groups, (CH₂)_(n)-heteroaryl groupsand (CH₂)_(n)-cycloalkyl groups, each of which may optionally besubstituted with one or more halo, alkyl, NO₂, haloalkyl and methoxygroups;R⁸ is selected from an alkyl group, an aryl group and a cycloalkyl groupeach of which may be optionally substituted by one or more of halo, CF₃,Me and OMe;R⁹, R¹⁰, R¹¹ are independently selected from H and alkyl; andR¹² is selected from H, alkyl, aryl and cycloalkyl; each of which may beoptionally substituted by one or more of halo, CF₃, Me and OMe.

In another preferred embodiment the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁶ is selected from a benzyl group which may be optionally substitutedwith one or more of halo, alkyl, NO₂, haloalkyl and alkoxy;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁶ is selected from a benzyl group which may be optionally substitutedwith one or more of halo, NO₂, CF₃, Me, tert-butyl and OMe;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁶ is selected from a benzyl group which may be optionally substitutedwith one or more of halo, NO₂, CF₃, Me and OMe;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁶ is selected from 3,5-di-tert-butyl-benzyl, 3,5-di-bromo-benzyl,3,5-di-methyl-benzyl, 3,5-bis(trifluoromethyl)benzyl,2-nitro-4,5-dimethoxybenzyl and benzyl;

R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment the catalyst is a compound of formula(VIIb) wherein M is selected from H, hydroxy, methoxy and R⁷;

R⁴ is selected from hydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl,C(═O)OR¹², amino, NR¹¹SO₂R¹², and R⁷;

Q is S;

R⁵ and R^(5a) are independently selected from H, methyl, ethyl, ethenyl;R⁶ is selected from 3,5-bis(trifluoromethyl)benzyl,2-nitro-4,5-dimethoxybenzyl and benzyl;R⁹ and R¹⁰ are H; and R⁸ is selected from an alkyl and aryl groupoptionally substituted by one or more of halo, CF₃, Me and OMe;

In another preferred embodiment the catalyst is selected from thefollowing:

wherein Y⁻ is a counterion. Examples of suitable counterions includefluoride, chloride, bromide and iodide. Preferably the counterion isbromide.

In another preferred embodiment the catalyst is selected from thosecatalysts in the preceding paragraph as well as the following:

wherein Y⁻ is a counterion. Examples of suitable counterions includefluoride, chloride, bromide and iodide. Preferably the counterion isbromide.

In another embodiment the catalyst is selected from those of thepreceding paragraph only.

In another embodiment the catalyst is selected from the following:

In another preferred embodiment the catalyst is selected from:

wherein R is independently selected from tert-butyl, CF₃, Me and Br, andM is selected from H and OMe; and wherein

indicates either a double bond or single bond.

In another preferred embodiment the catalyst is selected from:

wherein R is selected from H and CF₃, R′ is selected from H and NO₂ andM is selected from H and OMe.

In another preferred embodiment the catalyst is selected from:

wherein R and R′ are independently selected from NO₂ and OMe, preferablyR′ is NO₂ or H and R is OMe or H.

In another preferred embodiment the catalyst is selected fromN-(3,5-ditrifluoromethylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)dihydroquinidinium bromide,N-(3,5-dimethylbenzyl)quinidinium bromide,N-(3,5-dibromobenzyl)quinidinium bromide, N-benzylcinchonidiniumbromide, N-(4,5-dimethoxy-2-nitrobenzyl)cinchonidinium bromide andN-(3,5-bis(trifluoromethyl)benzyl)cinchonidinium bromide,N-benzylquinidinium bromide, N-(2-nitro-4,5-dimethoxybenzyl)quinidiniumbromide.

In another preferred embodiment the catalyst is selected fromN-benzylcinchonidinium bromide,N-(4,5-dimethoxy-2-nitrobenzyl)cinchonidinium bromide andN-(3,5-bis(trifluoromethyl)benzyl)cinchonidinium bromide,N-benzylquinidinium bromide, N-(2-nitro-4,5-dimethoxybenzyl)quinidiniumbromide. In another embodiment the catalyst is selected fromN-(3,5-ditrifluoromethylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)dihydroquinidinium bromide,N-(3,5-dimethylbenzyl)quinidinium bromide,N-(3,5-dibromobenzyl)quinidinium bromide. Preferably the catalyst isselected from N-benzylquinidinium bromide,N-(4,5-dimethoxy-2-nitrobenzyl)quinidinium bromide.

In another embodiment the catalyst is selected fromN-(3,5-ditrifluoromethylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)dihydroquinidinium bromide,N-(3,5-dimethylbenzyl)quinidinium bromide,N-(3,5-dibromobenzyl)quinidinium bromide, N-benzylcinchonidiniumbromide, N-(4,5-dimethoxy-2-nitrobenzyl)cinchonidinium bromide andN-(3,5-bis(trifluoromethyl)benzyl)cinchonidinium bromide,N-benzylquinidinium bromide, N-(2-nitro-4,5-dimethoxybenzyl)quinidiniumbromide and tetrabutylammonium bromide, tetraethylammonium bromide,triphenylbutylammonium bromide, trimethylphenylphosphonium bromide andtetrabutylphosphonium bromide.

Throughout the specification, where substituents M, R⁴, R⁵, R^(5a), R⁶,R⁸ to R¹⁴ are defined as optionally substituted, examples of suitablesubstituents may include one or more of hydroxy, alkyl, aryl, halo,alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, nitro and cycloalkyl.Preferably, suitable substitutents are selected from one or more ofhydroxy, alkyl, alkoxy, halo, haloalkoxy, nitro and aryl. Morepreferably, suitable substitutents are selected from one or morehydroxy, methyl, ethyl, methoxy, ethoxy, halo, NO₂, CF₃ and phenylgroups.

It will be appreciated by a person skilled in the art that the some ofthe above catalysts possess at least two chiral centres and thus giverise to diastereoisomers. Where stereochemistry is not specificallyindicated it will be understood that all diastereoisomers areencompassed by the structures shown.

Preferably the catalysts are those of formulae VIIa-d which providecompounds of formula (V) with the S-configuration at the chiral centredenoted by *.

In one embodiment the catalyst loading with respect to the compound offormula (IV) is less than or equal to about 1:1. In another embodimentthe catalyst loading with respect to the compound of formula (IV) isless than or equal to about 0.5:1. In another embodiment the catalystloading with respect to the compound of formula (IV) is less than orequal to about 0.2:1. Preferably, the catalyst loading with respect tothe compound of formula (IV) is about 0.05:1.

The Processes

In one aspect, the present invention provides a process for thepreparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof:

which process comprises the step of preparing a compound of formula (IV)by reacting a compound of formula (III) with a compound of formula (II):

wherein R¹, R², and X are as defined herein above.

In one embodiment the reaction comprises a base. Preferably the baseprovides a source of hydroxide. Examples of suitable bases may includesodium hydroxide, lithium hydroxide and potassium hydroxide. Preferably,the base is sodium hydroxide.

Preferably, the reaction is conducted in the presence of an aqueoussolvent, such as water, or a mixture of solvents comprising water.Preferably the solvent comprises water and a C₁₋₆ alcohol, such asmethanol or ethanol.

In another embodiment, the reaction comprises a further organic solvent.The further organic solvent may be selected from tetrahydrofuran,1,4-dioxan, diethyl ether. Preferably, the further organic solvent istetrahydrofuran.

In one embodiment the ratio of water to C₁₋₆ alcohol is between 0.1:1and 100:1. In another embodiment the ratio of water to C₁₋₆ alcohol isbetween 0.1:1 and 50:1. In another embodiment the ratio of water to C₁₋₆alcohol is between 0.1:1 and 20:1. In another embodiment the ratio ofwater to C₁₋₆ alcohol is between 1:1 and 20:1.

Preferably, the solvent is 9:1 water to C₁₋₆ alcohol. Preferably theC₁₋₆ alcohol is ethanol or methanol.

In another embodiment, the solvent is 7:3 water to C₁₋₆ alcohol.Preferably the C₁₋₆ alcohol is methanol.

Optionally, the coupling of a compound of formula (III) and a compoundof formula (II) and subsequent dehydration to yield a compound offormula (IV) can be carried out in two stages with isolation of theintermediate compound of formula (IIIa) (Scheme 4).

The dehydration stage may be carried out by first activating thehydroxyl group of a compound of formula (IIIa) using any method commonlyknown in the art. In one embodiment, the hydroxyl group is mesylatedwith mesyl chloride in the presence of triethylamine. Elimination ofmethanesulfonic acid yields a compound of formula (IV).

Preferably the dehydration is carried out in the presence of a solvent.In one embodiment the solvent is selected from dichloromethane,tetrahydrofuran, 1,4-dioxan, diethylether, toluene, acetone, ethylacetate. Preferably the solvent is dichloromethane.

In an alternative aspect the present invention provides a process forthe preparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof:

wherein:R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;which process comprises preparing a compound of formula (IV) by reactinga compound of formula (IIIA) with a compound of formula (II) to form acompound of formula (IIIB):

wherein:L is a hydroxyl activating group, R¹ is defined above in relation to thecompound of formula (I); and R² is an alkyl group or aryl group, each ofwhich may be optionally substituted; and converting the compound offormula (IIIB) to a compound of formula (IIIC):

wherein:X is an electron withdrawing group; and converting the compound offormula (IIIC) to a compound of formula (IV).

In one embodiment the reaction of (II) and (IIIA) is carried out in thepresence of a base, such as LDA. In one embodiment the reaction of (II)and (IIIA) is carried out in the presence of a base and then thehydroxyl activating group is added with or without isolation of theintermediate hydroxyl compound.

In a preferred embodiment X in the compounds of formula (IIIB) and(IIIC) is nitro. In such an embodiment, suitable reagents for generationof NO2+ will be apparent to the skilled person. Exemplary conditionsinclude HNO₃/H₂SO₄ and tetramethyl ammonium nitrate and trifluoroacetycanhydride.

The conversion of the compound of formula (IIIC) to the compound offormula (IV) may be carried out by any method known in the art.Preferably the reaction is carried out in the presence of an organicbase, preferably the reaction is carried out in the presence of an aminesuch as triethylamine.

In one embodiment the process further comprises the step of reacting acompound of formula (IV) with nitromethane in the presence of a catalystto provide a compound of formula (V):

wherein R¹, R² and X are as defined hereinabove.

In one embodiment the reaction of the compound of formula (IV) withnitromethane is carried out in the presence of a base. Preferably thebase is a source of carbonate. Examples of suitable bases include, butare not limited to, potassium carbonate, sodium carbonate and cesiumcarbonate. Preferably the base is potassium carbonate.

In one embodiment the reaction of the compound of formula (IV) withnitromethane is carried out in a solvent. Examples of suitable solventsinclude tetrahydrofuran, 1,4-dioxan, toluene and xylene. Preferably, thesolvent is toluene. In one embodiment the solvent is toluene recycledfrom previous reactions comprising reacting a compound of formula (IV)with nitromethane in the presence of a catalyst to provide a compound offormula (V).

In one embodiment the reaction of the compound of formula (IV) withnitromethane is conducted at a temperature of between −70° C. to 30° C.In another embodiment the reaction is conducted at a temperature ofbetween −70° C. to 0° C. In another embodiment the reaction is conductedat a temperature of between −50° C. to −20° C. Preferably the reactionis conducted at a temperature of about −37° C.

In one embodiment the reaction of the compound of formula (IV) withnitromethane is conducted at a temperature of between −70° C. to 50° C.In another embodiment the reaction is conducted at a temperature ofbetween 0° C. to 30° C. In another embodiment the reaction is conductedat a temperature of between 20° C. to 30° C. Preferably the reaction isconducted at room temperature.

In one embodiment the reaction of the compound of formula (IV) withnitromethane provides a compound of formula (V) with an enantiomericexcess of greater than about 60%. In another embodiment the enantiomericexcess is greater than about 70%. In another embodiment the enantiomericexcess is greater than about 80%. Preferably the enantiomeric excess isgreater than about 90%.

In one embodiment compound of formula (V) is enantiomerically enrichedby re-crystallization. In one embodiment re-crystallization is inisopropanol or mixtures of isopropanol and hexane.

In one embodiment the enantiomerically enriched compound of formula (V)has an enantiomeric excess of greater than about 90%, more preferablygreater than about 95%, more preferably greater then about 99%.

In one embodiment the process further comprises the step of hydrolysingthe compound of formula (V) to provide a compound of formula (VI)

wherein R¹, R² and X are as defined hereinabove.

In one embodiment the process further comprises the step of hydrolysingthe compound of formula (VIb) to provide a compound of formula (I)

wherein R¹, R² and X are as defined hereinabove; with the proviso that Xis not NO₂.

The hydrolysis may be carried out by any method commonly known in theart.

In one embodiment the hydrolysis of compound (V) or (VIb) is carried outin the presence of a base. Preferably the base is a source of hydroxide.Examples of suitable bases include, but are not limited to, sodiumhydroxide, potassium hydroxide and lithium hydroxide. Preferably thebase is sodium hydroxide, more preferably aqueous sodium hydroxide.

The hydrolysis may be performed in the presence of an organic solvent.Examples of suitable organic solvent include, but are not limited to,tetrahydrofuran, 1,4-dioxan and diethyl ether. Preferably the solvent istetrahydrofuran.

In one embodiment the solvent is a mixture of organic solvent and water.Preferably, the solvent is a mixture of water and tetrahydrofuran.

In one embodiment the process further comprises the step of reducing thecompound of formula (VI) to provide a compound of formula (I)

wherein R¹, R² and X are as defined hereinabove.

In one embodiment the process further comprises the step of reducing thecompound of formula (V) to provide a compound of formula (VIb)

wherein R¹, R² and X are as defined hereinabove; with the proviso that Xis not NO₂.

The reduction may be accomplished by any commonly known method in theart. Examples of suitable reduction reactions include, but are limitedto, hydrogenation, transfer hydrogenation or transition metal and acidreduction.

Preferably the reduction of a compound of formula (VI) or (V) isaccomplished by catalytic hydrogenation. Optionally, the hydrogenationis conducted in the presence of an acid. Preferably the acid ishydrochloric acid.

Preferred hydrogenation catalysts include palladium on carbon and Raneynickel.

In one embodiment the reduction is conducted in a solvent. Suitablesolvents include, but are not limited to ethanol, methanol and ethylacetate. Preferably the solvent is ethanol.

In one embodiment the reduction may be performed accordingly to theprocedure described in F. Felluga, G. Pitacco, E. Valentin, C. D.Venneri Tetrahedron: Asymm, 2008, 945.

In another aspect of the invention there is provided a process for thepreparation of a compound of formula (IV), and salts thereof, whichprocess comprises reacting a compound of formula (III) with a compoundof formula (II):

as described hereinabove,wherein R¹, R² and X are as defined above.

In another aspect of the invention, there is provided the use of acompound of formula (IV)

wherein R¹, R² and X are as defined above in the preparation of acompound of formula (I).

Another aspect of the invention relates to a process for the preparationof a compound of formula (I), and pharmaceutically acceptable salts,solvates and prodrugs thereof:

wherein:

R¹ is selected from an alkyl group, an alkenyl group, an alkynyl groupand a cycloalkyl group, each of which may be optionally substituted;and * denotes a chiral centre;

which process comprises the step of reacting a compound of formula (IV)with nitromethane in the presence of a catalyst to provide a compound offormula (V);

wherein:R¹ and * are as defined above in relation to the compound of formula(I); R² is an alkyl group or aryl group, each of which may be optionallysubstituted; and X is an electron withdrawing group.

In one embodiment the reaction is carried out in the presence of a base.Preferably the base is a source of carbonate. Examples of suitable basesinclude, but are not limited to, potassium carbonate, sodium carbonateand cesium carbonate. Preferably the base is potassium carbonate.

In one embodiment the reaction is carried out in a solvent. Examples ofsuitable solvents include tetrahydrofuran, 1,4-dioxan, toluene andxylene. Preferably, the solvent is toluene. In one embodiment thesolvent is toluene recycled from previous reactions comprising reactinga compound of formula (IV) with nitromethane in the presence of acatalyst to provide a compound of formula (V).

In one embodiment the reaction is conducted at a temperature of between−70° C. to 30° C. In another embodiment the reaction is conducted at atemperature of between −70° C. to 0° C. In another embodiment thereaction is conducted at a temperature of between −50° C. to −20° C.Preferably the reaction is conducted at a temperature of about −37° C.

In one embodiment the reaction is conducted at a temperature of between−70° C. to 50° C. In another embodiment the reaction is conducted at atemperature of between 0° C. to 30° C. In another embodiment thereaction is conducted at a temperature of between 20° C. to 30° C.Preferably the reaction is conducted at room temperature.

In an alternative aspect the present invention provides a process forthe preparation of a compound of formula (I), and pharmaceuticallyacceptable salts, solvates and prodrugs thereof:

which process comprises the step of reacting a compound of formula (IIA)with a compound of formula (III) in the presence of a catalyst toprovide a compound of formula (V);

wherein R¹, R² and X are as defined hereinabove.

In one embodiment the reaction of the compound of formula (IIA) with acompound of formula (III) is carried out in the presence of a base.Preferably the base is a source of carbonate. Examples of suitable basesinclude, but are not limited to, potassium carbonate, sodium carbonateand cesium carbonate. Preferably the base is potassium carbonate.

In one embodiment the reaction provides a compound of formula (V) withan enantiomeric excess of greater than about 60%. In another embodimentthe enantiomeric excess is greater than about 70%. In another embodimentthe enantiomeric excess is greater than about 80%. Preferably theenantiomeric excess is greater than about 90%.

In one embodiment compound of formula (V) is enantiomerically enrichedby re-crystallization. In one embodiment re-crystallization is inisopropanol or mixtures of isopropanol and hexane.

In one embodiment the enantiomerically enriched compound of formula (V)has an enantiomeric excess of greater than about 90%, more preferablygreater than about 95%, more preferably greater then about 99%

In one embodiment the compound of formula (IV) may be prepared byreacting a compound of formula (III) with a compound of formula (II):

as described hereinabove.

In alternative embodiment the compound of formula (IV) may be preparedby reacting a compound of formula (IIIA) with a compound of formula (II)to form a compound of formula (IIIB):

and converting the compound of formula (IIIB) to a compound of formula(IIIC):

and converting the compound of formula (IIIC) to a compound of formula(IV), as described hereinabove.

In one embodiment the compound of formula (V) may be prepared byreacting a compound of formula (IIA) with a compound of formula (III) inthe presence of a catalyst;

as described hereinabove.

In one embodiment the process further comprises the step of hydrolysingthe compound of formula (V) to provide a compound of formula (VI)

as described hereinabove.

In one embodiment the process further comprises the step of hydrolysingthe compound of formula (VIb) to provide a compound of formula (I);

wherein R¹, R² and X are as defined hereinabove; with the proviso that Xis not NO₂, as described hereinabove.

In one embodiment the process further comprises the step of reducing thecompound of formula (VI) to provide a compound of formula (I)

as described herein above.

In one embodiment the process further comprises the step of reducing thecompound of formula (V) to provide a compound of formula (VIb);

wherein R¹, R² and X are as defined hereinabove; with the proviso that Xis not NO₂, as described hereinabove.

In another aspect of the invention there is provided a process for thepreparation of a compound of formula (V), and salts thereof, whichprocess comprises reacting a compound of formula (IV), with nitromethanein the presence of a catalyst:

as described hereinabove,wherein R¹, R² and X are as defined above.

In another aspect of the invention, there is provided the use of acompound of formula (V)

wherein R¹, R² and X are as defined above, in the preparation of acompound of formula (I).

In the processes of the present invention the compound of formula (I)preferably has an enantiomeric excess of greater than about 60%. Inanother embodiment the enantiomeric excess is greater than about 70%. Inanother embodiment the enantiomeric excess is greater than about 80%. Inanother embodiment the enantiomeric excess is greater than about 90%. Inanother embodiment the enantiomeric excess is greater than about 95%. Inanother embodiment the enantiomeric excess is greater than about 99%.

In one embodiment compound of formula (I) is enantiomerically enrichedby resolution. Any suitable resolving agent may be used, for exampletartaric acid based resolving agents, mandelic acid based resolvingagents and enzymes.

In one embodiment the enantiomerically enriched compound of formula (I)has an enantiomeric excess of greater than about 90%, more preferablygreater than about 95%, more preferably greater then about 99%

EXAMPLES

The following examples are intended to illustrate particular embodimentsof the invention, and are not intended to limit the specification,including the claims in any manner.

It will be apparent to those skilled in the art that many modifications,both to the materials and the methods, may be made without departingfrom the spirit or scope of the invention.

Experimental

Part A—Preparation of3-methyl-5-(4-methyl-pent-1-enyl)-4-nitro-isoxazole (8)

In a round bottomed flask fitted with a magnetic stirrer were dissolved1.4 mmol of 3,5-dimethyl-4-nitroisoxazole 1 (200 mg) in water ethanolmixture (9:1, 0.8 mL). To the clear solution was added NaOH powder (40mg, 1.4 mmol, 1 equiv). The solution turned deep yellow and was stirredat room temperature for 30 minutes before aldehyde 2 (146 mg, 1.7 mmol)was added in one portion. The reaction mixture was then stirred at roomtemperature for seven days, then quenched with saturated ammoniumchloride and compound 8 extracted with dichloromethane (5 mL). Theorganic layer was washed with water (3×10 mL) and carried through thenext step without further purification (290 mg, 1.26 mmol, 90% yield).Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.23-4.20 (1H, m), 3.36 (1H, dd, J=15 J=4), 3.29(1H, dd, J=15 J=7), 2.55 (3H, s), 1.87-1.76 (1H, m), 1.58-1.53 (1H, m),1.40-1.34 (1H, m), 0.95 (3H, d, J=7), 0.93 (3H, d, J=7); δ_(c) (100.6MHz, CDCl₃) 172.9, 155.8, 130.9, 68.0, 46.8, 36.1, 24.8, 23.3, 22.0,11.8. HRMS: m/z found [M+H]⁺229.1154, C₁₀H₁₇N₂O₃ requires 229.1188.

Part (A) preparation of4-methyl-1-(3-methyl-4-nitro-isoxazol-5-yl)-pentan-2-ol (8)

In a 1000 mL conical flask fitted with a magnetic follower were put3,5-dimethyl-4-nitroisoxazole 1 (100 g, Mw=142, 704.2 mmol) and 150 mLof THF and the resulting solution stirred at 0° C. To this solution,were then added 200 mL of MeOH:H₂O (7:3). A freshly made solution ofNaOH (5 g, Mw=40, 125 mmol) in 50 mL of H₂O was then charged in adropping funnel and added drop wise over 10 minutes. Upon this addition,the solution becomes yellow to dark brown. It was noted the formation ofa precipitate of sodium 3,5-dimethyl-4-nitroisoxazolate that willdissolve during the course of the reaction. At this point, a solution ofisovaleraldehyde 2 (151 g, Mw=86, 1755 mmol, 2.5 equiv.) in 100 mL ofTHF was added drop wise at 0° C. over the period of 50 min. After thisperiod the ice bath was removed and the reaction allowed reaching roomtemperature under vigorous stirring. Conversion was monitored after 2 h(60%), 3 h (83%), 3 h30 min (92%) since end of addition of aldehyde. Asample of the reaction mixture was kept under stirring for further twohours and conversion measured again (92%) indicating the reactionmixture had reached the equilibrium. The reaction was quenched withdistilled H₂O (500 mL), stirred for 10 minutes, then extracted twicewith DCM (300 mL+200 mL). The organic layers were combined, washed withH₂O (300 mL at least to avoid formation of emulsion), then with satNaHSO₃ (200 mL) then again with H₂O (300 mL). The organic layer wasevaporated at the rotavapor (49° C., 44 mb) to give 161 g of materialwhich contains the title compound alongside 7% of alkene 3, 8% of3,5-dimethyl-4-nitroisoxazole and 5% of isovaleraldehyde. Estimatedweight in title alcohol was 146 g (91% yield). Colorless liquid;R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10); δ_(H) (400 MHz, CDCl₃)4.23-4.20 (1H, m), 3.36 (1H, dd, J=15 J=4), 3.29 (1H, dd, J=15 J=7),2.55 (3H, s), 1.87-1.76 (1H, m), 1.58-1.53 (1H, m), 1.40-1.34 (1H, m),0.95 (3H, d, J=7), 0.93 (3H, d, J=7); δ_(c) (100.6 MHz, CDCl₃) 172.9,155.8, 130.9, 68.0, 46.8, 36.1, 24.8, 23.3, 22.0, 11.8. HRMS: m/z found[M+H]⁺229.1154, C₁₀H₁₇N₂O₃ requires 229.1188.

Part (B) preparation of3-methyl-5-(4-methyl-pent-1-enyl)-4-nitro-isoxazole (3)

To a solution of alcohol 8 (39 mg, 0.17 mmol) in dichloromethane (1 mL)kept at 0° C. by an ice-water bath was added methanesulfonyl chloride(30 mg, 0.20 mmol, 1.2 equiv) and then triethylamine (34.4 mg, 0.34mmol, 2 equiv). The reaction was allowed to reach room temperature andthen stirred for 1 hour. Then the reaction mixture was quenched withwater (2 mL), the organic layer was extracted with dichloromethane (3×3mL), washed with brine, dried over anhydrous Na₂SO₄ filtered andevaporated to give pure compound 3 (35 mg, 99% yield). Colorless liquid;R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10); δ_(H) (400 MHz, CDCl₃)7.12-7.00 (2H, m), 2.56 (3H, s), 2.29-2.26 (2H, m), 1.89-1.82 (1H, m),0.97 (6H, d, J=6), δ_(c) (100.6 MHz, CDCl₃) 167.0, 156.0, 130.1, 115.6,43.0, 28.3, 22.5, 12.0. HRMS: m/z found [M]⁺196.0815, C₉H₁₄N₂O₃ requires196.0848.

Part (B) preparation of3-methyl-5-(4-methyl-pent-1-enyl)-4-nitro-isoxazole (3)

In a 3 L round bottomed flask fitted with an overhead stirrer (toovercome difficult stirring caused by formation of solid HNEt₃Cl throughthe reaction) were loaded 160 g of4-methyl-1-(3-methyl-4-nitro-isoxazol-5-yl)-pentan-2-ol 8 (about 90%pure, 144 g, 633 mmol, Mw=229) and 1000 mL of DCM. The solution wascooled at −30° C. by adding liquid nitrogen to a methanol bath, thenmethanesulfonyl chloride (86.62 g, Mw=114, 760 mmol, 1.2 equiv) wasadded drop wise in 20 min. To the resulting solution was then added NEt₃(127.9 g, 1266 mmol, Mw=101, 2.0 equiv) drop wise over the period of 1h15 min while maintaining the temperature between 0° C. and −20° C.After the addition was completed the reaction was allowed to reach roomtemperature and stirred for 2 h (from the end of addition of NEt₃). Thereaction was quenched with H₂O (300 mL), washed with additional H₂O(2×500 mL), then with 5% NaOH in water, the organic layer dried overNa₂SO₄ and then evaporated under reduced pressure (47° C., 0 mb) to give163 g of crude product which was thinned with 50 mL of petroleum ether(40-60° C.) and passed through a plug of silica gel (flash type) (10 g)eluting with petroleum ether (40:60) (50 mL) to give 132 g of titlecompound. Estimated purity of alkene is 92%. Pale yellow liquid; R_(f)⁼0.8 (Petroleum Ether/Ethyl Acetate, 90:10); δ_(H) (400 MHz, CDCl₃)7.12-7.00 (2H, m), 2.56 (3H, s), 2.29-2.26 (2H, m), 1.89-1.82 (1H, m),0.97 (6H, d, J=6), δ_(c) (100.6 MHz, CDCl₃) 167.0, 156.0, 130.1, 115.6,43.0, 28.3, 22.5, 12.0. HRMS: m/z found [M]⁺196.0815, C₉H₁₄N₂O₃ requires196.0848.

Note 1:

Product 3 was obtained over 99.9% pure via distillation, collecting thefraction boiling over 120° C. at 0.2 mb. The yield was ca 65-70% of purealkene.

Note 2:

Purification via DMF wash: the alkene 3 may be obtained over 99.9% pureby dissolving it in a DMF:H₂O (20:80) and then extracting with petroleumether. Typically, 12 g of crude material were dissolved in 10 mL of DMF,then 40 mL of water were added and the resulting yellow solution wasextracted with petroleum ether (40:60), (2×50 mL). Optionally, thealkene (20 g) was dissolved in petroleum ether (40:60), (50 mL), thentreated with 3 mL of DMF, stirred for 20 minutes, then washed with water(2×50 mL).

Alternative Synthesis of Alkenes 3′

An alternative route to styrylisoxazoles 3′a-d involves reaction of3,5-dimethylisoxazole 1 with LDA followed by addition of suitablealdehydes 2′a-d. The resulting alcohols 8′a-d were mesylated using MsCland triethylamine to give compounds 104a-d which in turn was nitrated to105a-d. Treatment of 105a-d with triethilamine gave desired 3′a-d.

TABLE 1 Isolated yields of hydroxyl isoxazoles 8′a-d Isolated EntryAldehyde Reactant Alk group Product yield (%) 1 2′a Cyclohexane 8′a 74 22′b CH(CH₂CH₃)CH₂CH₂CH₂CH₃ 8′b 55 3 2′c CH₂CH(CH₃)₂ 8′c 70 4 2′dCH₂CH₂CH₂CH₂CH₂CH₃ 8′d 64

TABLE 2 Isolated yields of mesylated isoxazoles 104a-d Isolated EntryStarter Reactant Alk group Product yield (%) 1 8′a Cyclohexane 104a 82 28′b CH(CH₂CH₃)CH₂CH₂CH₂CH₃ 104b 88 3 8′c CH₂CH(CH₃)₂ 104c 85 4 8′dCH₂CH₂CH₂CH₂CH₂CH₃ 104d 90

TABLE 3 Isolated yields of nitro isoxazoles 105a-d Isolated StarterReactant Alk Product yield (%) 1 104a Cyclohexane 105a 79 2 104bCH(CH₂CH₃)CH₂CH₂CH₂CH₃ 105b 75 3 104c CH₂CH(CH₃)₂ 105c 70 4 104dCH₂CH₂CH₂CH₂CH₂CH₃ 105d 80

TABLE 4 Isolated yields of aliphatic nitro isoxazoles 3′a-d IsolatedStarter Reactant Alk Product yield (%) 1 105a Cyclohexane 3′a 82 2 105bCH(CH₂CH₃)CH₂CH₂CH₂CH₃ 3′b 88 3 105c CH₂CH(CH₃)₂ 3′c 92 4 105dCH₂CH₂CH₂CH₂CH₂CH₃ 3′d 89Typical Procedure for Preparation of Hydroxy Isoxazoles (Compounds8′a-d)

Under an inert atmosphere, lithium diisopropyl amide (5 ml, 10 mmol) wasadded dropwise to a stirred solution of isoxazole (1 g, 10 mmol) inanhydrous tetrahydrofuran (10 mL) at −78° C. using a liquidnitrogen/acetone bath. The resulting solution was stirred at the sametemperature for 60 minutes. To this solution was then added thealiphatic aldehyde (1 eq, 10 mmol)-78° C. over 60 minutes. The resultingreaction mixture was allowed to warm to room temperature over a periodof 2 h, with stirring magnetically. At the end of this time the solventwas evaporated off and the residue re-dissolved in DCM, quenched withsaturated aqueous ammonium chloride solution (10 mL) and extracted withDCM (2×20 mL). Combined organic extracts were washed with water followedby brine and dried over anhydrous sodium sulphate before evaporationunder reduced pressure. The crude product was purified by columnchromatography with 10% ethyl acetate in petroleum spirits as an eluentfollowed by 20% ethyl acetate in petroleum ether to afford the puretitle product.

1-Cyclohexyl-2-(3-methyl-isoxazol-5-yl)-ethanol 8′a

1.5 g, 74% yield, yellow oil, R_(f)=0.4 (30%, EtOAc in Petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.91 (1H, s, C═C—H), 3.61-3.69(1H, m, CH₂CH), 2.84 (1H, dd, J=15, J=4, CH ₂CH), 2.74 (1H, dd, J=15,J=9, CH ₂CH), 2.18 (3H, s, CH ₃C═N), 1.82-1.59 (5H, m, H Aliphatic),1.35-1.27 (1H, m, H Aliphatic), 1.23-0.93 (5H, m, H Aliphatic); ¹³C NMR(100.6 MHz) δ_(c)=168.1 (C═C—H), 160.0 (N═C—CH₃), 103.3, (C═C—H), 73.9(C—OH), 38.3 (CH-cyclohexane), 34.9 (CH₂-aliphatic), 29.1(CH₂-cyclohexane), 27.8 (CH₂-cyclohexane), 26.2 (CH₂-cyclohexane), 14.0(CH₃-aliphatic), 14.0 (CH₃-aliphatic), 11.4 (N═C—CH₃), HRMS found:[M−H⁺] 209.152, C₁₂H₁₈NO₂ requires 209.146; m/z: 209 (100%, M−H⁺).

3-Ethyl-1-(3-methyl-isoxazol-5-yl)-heptan-2-ol 8′b

1.24 g, 55% yield, yellow oil, R_(f)=0.39 (30%, EtOAc in Petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.91 (1H, s, C═C—H), 3.61-3.69(1H, m, CH₂CH), 2.84 (1H, dd, J=15, J=4, CH ₂CH), 7.74 (1H, dd, J=15,J=9, CH ₂CH), 2.18 (3H, s, CH ₃C═N), 1.82-1.59 (5H, m, H Aliphatic),1.35-1.27 (1H, m, H Aliphatic), 1.23-0.93 (5H, m, H Aliphatic),0.92-0.82 (6H, m, (CH ₃)₂); ¹³C NMR (100.6 MHz) δ_(c)=170.94 (C═C—H),159.9 (N═C—CH₃), 103.0, (C═C—H), 71.4 (C—OH), 46.97 (CH-aliphatic), 44.9(CH₂-aliphatic), 30.6 (CH₂-aliphatic), 28.2 (CH₂-aliphatic), 23.4(CH₂-aliphatic), 21.3 (CH₂-aliphatic), 14.0 (CH₃-aliphatic), 14.0(CH₃-aliphatic), 11.7 (N═C—CH₃); HRMS found: [M−H⁺] 225.1733, C₁₃H₂₃NO₂requires 225.1729; m/z: 225 (100%, M−H⁺).

4-Methyl-1-(3-methyl-isoxazol-5-yl)-pentan-2-ol 8′c

1.28 g, 70% yield, yellow oil, R_(f)=0.4 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.92 (1H, s, {acute over (H)}isoxazole), 4.06-4.00 (1H, m CH₂—CH), 2.87 (1H, dd, J=15, J=4, CH ₂CH),2.79 (1H, dd, J=15, J=8, CH ₂CH), 2.25 (3H, s, N═C—CH ₃), 1.84-1.74 (1H,m, CH aliphatic), 1.49-1.42 (1H, m, CH aliphatic), 1.30-1.23 (1H, m, CHaliphatic), 0.91 (6H, t, J=7, CH(CH ₃)₂, 13C NMR (100.6 MHz) δ_(c)=170.2(C═C—H), 159.9 (N═C—CH₃), 103.2, (C═C—H), 67.95 (C—OH), 46.05(CH₂-aliphatic), 35.4 (CH₂-aliphatic), 23.3 (CH₃-aliphatic), 21.9(CH-aliphatic), 11.4 (CH₃-aliphatic), 11.4 (N═C—CH₃), HRMS found: [M−H⁺]183.1262, C₁₀H₁₇NO₂ requires 183.1259; m/z: 183 (100%, M−H⁺).

1-(3-Methyl-isoxazol-5-yl)-octan-2-ol; compound with methane 8′d

1.35 g, 64% yield, yellow oil, R_(f)=0.42 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.87 (1H, s, C═C—H), 3.91-3.85(1H, m, CH₂CH), 2.82 (1H, dd, J=15, J=5, CH ₂CH), 2.75 (1H, dd, J=15,J=8, CH ₂CH), 2.18 (3H, s, CH ₃C═N), 1.46-1.34 (5H, m, H Aliphatic),1.34-1.21 (5H, m, H Aliphatic), 0.91-0.87 (3H, t, J=6, (CH ₃); ¹³C NMR(100.6 MHz) δ_(c)=170.94 (C═C—H), 159.9 (N═C—CH₃), 104.1, (C═C—H), 80.6(C—OH), 38.35 (CH₂-aliphatic), 34.48 (CH₂-aliphatic), 31.7(CH₂-aliphatic), 28.2 (CH₂-aliphatic), 25.2 (CH₂-aliphatic), 21.3(CH₂-aliphatic), 14.0 (CH₃-aliphatic), 11.4 (N═C—CH₃); HRMS found:[M−H⁺] 211.1564, C₁₂H₂₁NO₂ requires 211.1572; m/z: 211 (100%, M−H⁺).

Typical Procedure for Preparation of Mesylated Isoxazoles (Compounds104a-d)

Methane sulfonyl chloride (25 mmol, 5 eq) and Et₃N (25 mmol, 5 eq) weresequentially added to a solution of starting alcohol (5 mmol, 1 eq) inDCM (10 ml) at 0° C. The reaction was then brought to room temperatureand stirred for a further hour. The mixture was then diluted with waterand the organic layer extracted, washed with brine and dried over MgSO₄before evaporation under reduced pressure. The crude product waspurified by column chromatography with 2% methanol in DCM as an eluentto afford the pure title product.

Methanesulfonic acid 1-cyclohexyl-2-(3-methyl-isoxazol-5-yl)-ethyl ester104a

1.180 g, 82% yield, yellow oil, R_(f)=0.5 (30%, EtOAc in Petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=6.00 (1H, s, C═C—H), 4.74 (1H,q, J=5.6, CH₂CH), 3.13 (2H, d, J=6, CH ₂CH), 2.83 (3H, s, SO2CH3), 2.27(3H, s, CH ₃C═N), 1.86-1.61 (6H, m, H Aliphatic), 1.29-1.15 (5H, m, HAliphatic); ¹³C NMR (100.6 MHz) δ_(c)=168.1 (C═C—H), 160.0 (N═C—CH₃),104.4, (C═C—H), 84.50 (C—OSO₂CH₃), 41.13 (C—OSO₂ CH₃), 38.3(CH-cyclohexane), 37.7 (CH₂-aliphatic), 29.3 (CH₂-cyclohexane), 28.3(CH₂-cyclohexane), 25.8 (CH₂-cyclohexane), 11.4 (N═C—CH₃); HRMS found:[M−H⁺] 287.1195, C₁₃H₂₁NO₄S requires 287.1191; m/z: 287 (100%, M−H⁺).

Methanesulfonic acid 2-ethyl-1-(3-methyl-isoxazol-5-ylmethyl)-hexylester 104b

1.33 g, 88% yield, yellow oil, R_(f)=0.52 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.97 (1H, s, C═C—H), 4.95-4.90(1H, m, CH₂CH), 3.04 (2H, d, J=6, CH ₂CH), 2.75 (3H, s, SO₂CH ₃), 2.21(3H, s, C═C—CH ₃), 1.65-1.58 (1H, m, CH aliphatic), 1.58-1.24 (8H, m,(CH ₂)₄ aliphatic), 0.92-0.82 (6H, m, (CH ₃)₂), ¹³C NMR (100.6 MHz)δ_(c)=170.94 (C═C—H), 159.9 (N═C—CH₃), 103.0, (C═C—H), 82.6 (C—OSO₂CH₃),46.76 (CH-aliphatic), 43.3 (CH₂-aliphatic), 38.3 (SO₂CH₃), 31.5(CH₂-aliphatic), 28.2 (CH₂-aliphatic), 25.2 (CH₂-aliphatic), 21.3(CH₂-aliphatic), 14.0 (CH₃-aliphatic), 14.0 (CH₃-aliphatic), 11.7(N═C—CH₃) HRMS found: [M−H⁺] 303.1512, C₁₄H₂₅NO₄S requires 303.1504;m/z: 303 (100%, M−H⁺).

Methanesulfonic acid 3-methyl-1-(3-methyl-isoxazol-5-ylmethyl)-butylester 104c

1.11 g, 85% yield, yellow oil, R_(f)=0.48 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.95 (1H, s, H isoxazole),4.97-4.92 (1H, m), 3.12 (1H, dd, J=16, J=5, CH ₂CH), 3.03 (1H, dd, J=16,J=6, CH ₂CH), 2.81 (3H, s, SO₂CH ₃), 2.21 (3H, s, N═C—CH ₃), 1.73-1.61(2H, m, CH₂ aliphatic), 1.42-1.38 (1H, m CH aliphatic), 0.89 (6H, t,J=7, CH(CH ₃)₂), 13C NMR (100.6 MHz) δ_(c)=170.1 (C═C—H), 158.2(N═C—CH₃), 103.2, (C═C—H), 68.0 (C—OSO₂CH₃), 46.1 (CH₂-aliphatic), 34.6(CH₂-aliphatic), 34.2 (SO₂CH ₃), 24.4 (CH₃-aliphatic), 23.9(CH₃-aliphatic), 22.3 (CH-aliphatic), 12.5 (N═C—CH₃), HRMS found: [M−H⁺]261.1039, C₁₁H₁₉NO₄S requires 261.1035; m/z: 261 (100%, M−H⁺).

Methanesulfonic acid 1-(3-methyl-isoxazol-5-ylmethyl)-heptyl ester 104d

1.3 g, 90% yield, yellow oil, R_(f)=0.5 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=6.02 (1H, s, C═C—H), 4.97-4.91(1H, m, CH₂CH), 3.15 (2H, dd, J=5, J=3, CH ₂CH), 2.89 (3H, s, SO₂CH ₃),2.29 (3H, s, C═C—CH ₃), 1.82-1.66 (2H, m, CH ₂ aliphatic), 1.48-1.24(8H, m, (CH ₂)₄ aliphatic), 0.91-0.87 (3H, t, J=6, (CH ₃), ¹³C NMR(100.6 MHz) δ_(c)=170.94 (C═C—H), 159.9 (N═C—CH₃), 104.1, (C═C—H), 80.6(C—OSO₂CH₃), 38.35 (SO₂CH₃), 34.48 (CH₂-aliphatic), 31.7(CH₂-aliphatic), 28.2 (CH₂-aliphatic), 25.2 (CH₂-aliphatic), 24.2(CH₂-aliphatic), 21.3 (CH₂-aliphatic), 14.0 (CH₃-aliphatic), 11.4(N═C—CH₃); HRMS found: [M−H⁺] 289.1350, C₁₃H₂₃NO₄S requires 289.1348;m/z: 289 (100%, M−H⁺).

Typical Procedure for Preparation of Nitro Isoxazoles (Compounds 105a-d)

Under a N₂ gas blanket at room temperature, triflic anhydride (2 mmol, 2eq) was added dropwise to a stirred suspension of tetra methyl ammoniumnitrate (2 mmol, 2 eq) in 2 ml of anhydrous DCM, a slight temperaturerise was observed. After stirring for at least 1.5 hours at roomtemperature, the stirred suspension was cooled to −78° C. using anacetone/liquid nitrogen bath. The aliphatic isoxazole (1 mmol, 1 eq) wasdissolved in 3 ml of anhydrous DCM and subsequently added to the stirrednitronium triflate suspension keeping the temperature at −65° C. orlower. The reaction suspension was kept under N₂, the cooling bathremoved and the reaction was stirred at room temperature for 24 hours.

The reaction was quenched using NaHCO₃ to give an aqueous layer of PH 8,the lower DCM layer was then separated and washed with 5×20 ml of water.The combined water washes were back extracted with 2×20 ml of DCM. Thecombined DCM portions were then dried over MgSO₄. DCM removal by rotaryevaporation gave the crude product. The crude product was purified bycolumn chromatography starting with 10% EtOAc in petroleum spirits asthe eluent followed by 20% EtOAc in petroleum spirits to give the pureproduct.

Methanesulfonic acid1-cyclohexyl-2-(3-methyl-4-nitro-isoxazol-5-yl)-ethyl ester 105a

0.26 g, 79% yield, yellow oil; R_(f)=0.65 (30%, EtOAc in Petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=4.97 (1H, m, CH₂CH), 3.60 (1H,dd, J=15, J=4, CH ₂CH), 3.47 (1H, dd, J=15, J=9, CH ₂CH), 2.91 (3H, s,SO₂CH ₃), 2.57 (3H, s, CH ₃C═N), 1.90-1.70 (6H, m, H Aliphatic),1.30-1.18 (5H, m, H Aliphatic); ¹³C NMR (100.6 MHz) δ_(c)=170.9(C═C—NO₂), 155.9 (N═C—CH₃), 110.9, (C═C—NO₂), 81.90 (C—OSO₂CH₃), 42.3(C—OSO₂ CH₃), 38.5 (CH-cyclohexane), 31.54 (CH₂-aliphatic), 30.7(CH₂-cyclohexane), 28.1 (CH₂-cyclohexane), 25.8 (CH₂-cyclohexane), 11.6(N═C—CH₃); HRMS found: [M−H⁺] 332.1035, C₁₃H₂₀N₂O₆S requires 332.1042;m/z: 332 (100%, M−H⁺).

Methanesulfonic acid2-ethyl-1-(3-methyl-4-nitro-isoxazol-5-ylmethyl)-hexyl ester 105b

0.26 g, 75% yield, yellow oil, R_(f)=0.62 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.20-5.16 (1H, m, CH₂CH), 3.48(2H, d, J=6, CH ₂CH), 2.88 (3H, s, SO₂CH ₃), 2.55 (3H, s, C═C—CH ₃),1.65-1.58 (1H, m, CH aliphatic), 1.58-1.24 (8H, m, (CH ₂)₄ aliphatic),0.92-0.82 (6H, m, (CH ₃)₂), ¹³C NMR (100.6 MHz) δ_(c)=171.05 (C═C—H),155.9 (N═C—CH₃), 103.0, (C═C—NO₂), 79.9 (C—OSO₂CH₃), 44.5(CH-aliphatic), 38.3 (SO₂CH₃), 31.54 (CH₂-aliphatic), 29.9(CH₂-aliphatic), 29.4 (CH₂-aliphatic), 28.57 (CH₂-aliphatic), 22.8(CH₂-aliphatic), 14.0 (CH₃-aliphatic), 14.0 (CH₃-aliphatic), 11.8(N═C—CH₃) HRMS found: [M−H⁺] 348.1360, C₁₄H₂₄N₂O₆S requires 348.1355;m/z: 348 (100%, M−H⁺).

Methanesulfonic acid3-methyl-1-(3-methyl-4-nitro-isoxazol-5-ylmethyl)-butyl ester 105c

0.21 g, 70% yield, yellow oil, R_(f)=0.67 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.23-5.17 (1H, m), 3.62 (1H,dd, J=15, J=4, CH ₂CH), 3.50 (1H, dd, J=15, J=8, CH ₂CH), 2.95 (3H, s,SO₂CH ₃), 2.58 (3H, s, N═C—CH₃), 1.84-1.75 (2H, m, CH₂ aliphatic),1.57-1.49 (1H, m CH aliphatic), 0.99 (6H, t, J=7, CH(CH ₃)₂), 13C NMR(100.6 MHz) δ_(c)=170.1 (C═C—H), 158.2 (N═C—CH₃), 103.2, (C═C—NO₂), 68.0(C—OSO₂CH₃), 46.1 (CH₂-aliphatic), 34.2 (SO₂CH ₃), 26.0 (CH₂-aliphatic),24.4 (CH₃-aliphatic), 23.9 (CH₃-aliphatic), 22.3 (CH-aliphatic), 12.5(N═C—CH₃), HRMS found: [M−H⁺] 306.0387, C₁₁H₁₈N₂O₆S requires 306.0386;m/z: 306 (100%, M−H⁺).

Methanesulfonic acid 1-(3-methyl-4-nitro-isoxazol-5-ylmethyl)-heptylester 105d

0.27 g, 80% yield, yellow oil, R_(f)=0.6 (30%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=5.06-5.01 (1H, m, CH₂CH), 3.54(1H, dd, J=15, J=4, CH ₂CH), 3.50 (1H, dd, J=15, J=8, CH ₂CH), 2.89 (3H,s, SO₂CH ₃), 2.51 (3H, s, C═C—CH ₃), 1.82-1.66 (2H, m, CH ₂ aliphatic),1.48-1.24 (8H, m, (CH ₂)₄ aliphatic), 0.89 (3H, t, J=6, (CH ₃), ¹³C NMR(100.6 MHz) δ_(c)=170.19 (C═C—H), 155.82 (N═C—CH₃), 102.21, (C═C—NO₂),78.05 (C—OSO₂CH₃), 38.35 (SO₂CH₃), 34.48 (CH₂-aliphatic), 31.7(CH₂-aliphatic), 29.6 (CH₂-aliphatic), 28.2 (CH₂-aliphatic), 25.2(CH₂-aliphatic), 22.50 (CH₂-aliphatic), 14.0 (CH₃-aliphatic), 11.81(N═C—CH₃); HRMS found: [M−H⁺] 334.1203, C₁₃H₂₂N₂O₆S requires 334.1199;m/z: 334 (100%, M−H⁺).

Typical Procedure for Preparation of Aliphatic Styrlisoxazoles(Compounds 3′a-d)

Et₃N (2.5 mmol, 2.5 eq) was added to nitro styryl isoxazole (1 mmol, 1.0eq) in DCM (15 ml) and stirred at room temperature for approximately 1hour. The reaction mixture was then quenched with NH₄Cl and diluted withwater (10 mL). The organic layer was separated and dried over Na₂SO₄,filtered and evaporated to yield the crude compound. The crude productwas purified by column chromatography using 100% DCM as the eluent.

5-(2-Cyclohexyl-vinyl)-3-methyl-4-nitro-isoxazole 3′a

0.19 g, 82% yield, yellow oil; R_(f)=0.75 (20%, EtOAc in Petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=6.97 (1H, dd, J=16, J=6,CH═CH), 6.91 (1H, d, J=16, CH═CH), 2.49 (3H, s, CH ₃C═N), 2.26-2.23 (1H,m, CH Aliphatic), 1.80-1.62 (5H, m, H Aliphatic), 1.34-1.11 (5H, m, HAliphatic); ¹³C NMR (100.6 MHz) δ_(c)=170.8 (C═C—NO₂), 156.0 (N═C—CH₃),111.1, (C═C—NO₂), 138.2 (C═C), 129.5 (C═C), 35.0 (CH-cyclohexane), 31.5(CH₂-cyclohexane), 27.5 (CH₂-cyclohexane), 25.0 (CH₂-cyclohexane), 11.4(N═C—CH₃); HRMS found: [M−H⁺] 236.1161, C₁₂H₁₆N₂O₃ requires 236.1161;m/z: 236 (100%, M−H⁺).

5-(3-Ethyl-hept-1-enyl)-3-methyl-4-nitro-isoxazole 3′b

0.22 g, 88% yield, yellow oil, R_(f)=0.77 (20%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): 6_(H)=6.94 (1H, d, J=16, CH═CH), 6.80(1H, dd, J=16, J=9, CH═CH), 2.49 (3H, s, N═C—CH ₃) 1.65-1.58 (1H, m, CHaliphatic), 1.58-1.24 (8H, m, (CH ₂)₄ aliphatic), 0.92-0.82 (6H, m, (CH₃)₂), ¹³C NMR (100.6 MHz) δ_(c)=171.05 (C═C—H), 155.9 (N═C—CH₃), 103.0,(C═C—NO₂), 135.6 (CH═CH), 136.9 (CH═CH), 40.3 (CH aliphatic), 31.54(CH₂-aliphatic), 29.4 (CH₂-aliphatic), 28.57 (CH₂-aliphatic), 22.8(CH₂-aliphatic), 14.0 (CH₃-aliphatic), 14.0 (CH₃-aliphatic), 11.8(N═C—CH₃) HRMS found: [M−H⁺] 252.1462, C₁₃H₂₀N₂O₃ requires 252.1474;m/z: 252 (100%, M−H⁺).

3-Methyl-5-(4-methyl-pent-1-enyl)-4-nitro-isoxazole 3′c

0.19 g, 92% yield, yellow oil, R_(f)=0.71 (20%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=7.08 (1H, dd, J=16, J=6,CH═CH), 7.03 (1H, dd, J=21, J=16, CH═CH), 2.53 (3H, s, N═C—CH ₃), 2.26(2H, t, J=6, CH₂ aliphatic), 1.89-1.79 (1H, m CH aliphatic), 0.95 (6H,d, J=7, CH(CH ₃)₂), ¹³C NMR (100.6 MHz) δ_(c)=170.1 (C═C—H), 158.2(N═C—CH₃), 133.0 (CH═CH), 127.0 (CH═CH), 103.2, (C═C—NO₂), 42.1(CH₂-aliphatic), 24.4 (CH₃-aliphatic), 23.9 (CH₃-aliphatic), 22.3(CH-aliphatic), 12.5 (N═C—CH₃), HRMS found: [M−H⁺] 210.1008, C₁₀H₁₄N₂O₃requires 210.1004; m/z: 210 (100%, M−H⁺)

3-Methyl-4-nitro-5-oct-1-enyl-isoxazole 3′d

0.21 g, 89% yield, yellow oil, R_(f)=0.75 (20%, EtOAc in petroleumspirits); ¹H NMR (400 MHz, CDCl₃): δ_(H)=7.10 (1H, dd, J=16, J=6,CH═CH), 7.06 (1H, dd, J=26, J=16, CH═CH), 2.54 (3H, s, C═C—CH ₃), 2.38(2H, q, J=6, CH₂ aliphatic), 1.57-1.50 (2H, m, CH ₂ aliphatic),1.37-1.28 (6H, m, (CH₂)₃), 0.89 (3H, t, J=6, (CH ₃), ¹³C NMR (100.6 MHz)δ_(c)=170.19 (C═C—H), 155.82 (N═C—CH₃), 135.6 (CH═CH), 126.9 (CH═CH),102.21, (C═C—NO₂), 34.48 (CH₂-aliphatic), 31.7 (CH₂-aliphatic), 28.2(CH₂-aliphatic), 25.2 (CH₂-aliphatic), 22.50 (CH₂-aliphatic), 14.0(CH₃-aliphatic), 11.81 (N═C—CH₃); HRMS found: [M−H⁺] 238.1302,C₁₂H₁₈N₂O₃ requires 238.1317; m/z: 238 (100%, M−H⁺).

Procedure for the preparation of3-methyl-5-(4-methyl-2-nitromethyl-pentyl)-4-nitro-isoxazole (5)

Procedure A:

In a round bottomed flask, fitted with a magnetic stirrer weresequentially added compound 3 (196 mg, 1 mmol) toluene (33 mL),N-benzyl-quinidinium bromide 4a(R═H) (23 mg, 0.05 equiv, 5 mol %), andnitromethane (300 mg, 5 mmol, 5 equiv). Finally, K₂CO₃ (690 mg, 5 mmol,1 equiv) was added in one portion. The reaction was stirred at 0° C. for60 hours, then quenched with sat NH₄Cl (10 mL), extracted with toluene(2×10 mL), dried over MgSO₄, filtered over celite and evaporated to givepure compound 5 in 96% yield and 65% ee.

Procedure B

In a round bottomed flask, fitted with a magnetic stirrer weresequentially added compound 3 (196 mg, 1 mmol) toluene (33 mL),N-(4,5-dimethoxybenzyl-2-nitrobenzyl)quinidinium bromide 4b (R═R₁═NO₂,R₂═OCH₃, R₃═OCH₃) (12 mg, 0.02 equiv, 2 mol %), and nitromethane (300mg, 5 mmol, 5 equiv). Finally, K₂CO₃ (690 mg, 5 mmol, 1 equiv) was addedin one portion. The reaction was stirred at 0° C. for 24 hours, thenquenched with sat NH₄Cl (10 mL), extracted with toluene (2×10 mL), driedover MgSO₄, filtered over celite and evaporated to give pure compound 5in 96% yield and 76% ee.

Compound 5: Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate,90:10); δ_(H) (400 MHz, CDCl₃) 4.38 (2H, d, J=6), 3.35 (1H, dd, J=15,J=6), 3.28 (1H, dd, J=15, J=7), 2.87 (1H, sept, J=7), 2.56 (3H, s), 1.68(1H, sept, J=7), 1.36-1.23 (2H, m), 0.92 (3H, d, J=4), 0.90 (3H, d,J=4), δ_(c) (100.6 MHz, CDCl₃) 172.1, 122.9, 78.5, 40.9, 33.9, 30.0,25.1, 22.4, 22.3, 11.7. HRMS: m/z found [M+H]⁺272.1212, C₁₁H₁₈N₃O₅requires 272.1212.

Recrystallisation of compound 5 from 68-86% ee to enantiopure +99ee:

Purified compound 5 (4 g) was dissolved in minimum amounts of hotisopropanol or hot mixtures of isopropanol hexane (1:1), which weretypically 3-10 mL. The resulting solution was cooled at −20° C. to givecompound 5 as needles, which were filtered, dried weighted 2.5-3.2 g.

Procedure C:

In a round bottomed flask, fitted with a magnetic stirrer weresequentially added alkene 3 (20 mg, 0.096 mmol) toluene (9.6 mL),catalyst A-E (see below) (0.1 equiv, 10 mol %), and nitromethane (30 mg,0.48 mmol, 5 equiv). The temperature was made 0° C. using an ice waterbath, then K₂CO₃ (66 mg, 0.48 mmol, 5 equiv) was added in one portion.The reaction was stirred at 0-3° C. for 32 hours, then quenched with satNH₄Cl (10 mL), extracted with toluene (2×10 mL), dried over MgSO₄,filtered over celite and evaporated to give pure compound in yield andee listed in table 1.

TABLE 1 catalyst screening entry Catalyst Conv % of 3 Yield % of 5 ee %of 5 1 A 100 95 72 2 B 100 97 86 3 C 100 96 85 4 D 100 97 64 5 E 100 9162

Procedure D:

In a round bottomed flask, fitted with a magnetic stirrer weresequentially added alkene 3 and toluene as indicated in table 2,catalyst B (0.05 equiv, 5 mol %) and nitromethane (3-5 equiv). Thetemperature was made 0° C. using an ice water bath, then K₂CO₃ (3-5equiv) was added in one portion. The reaction was stirred at 0-3° C. fortime indicated in table 2, then quenched with sat NH₄Cl, extracted withtoluene, dried over MgSO₄, filtered over celite and evaporated to givepure compound in yield and ee as listed in table 2.

TABLE 2 Alkene Alkene Conc. Toluene Conv. % Ee % Entry CH₃NO₂ K₂CO₃ 3(mmol) 3(mg) (M) (mL) of 3 of 5 1 5 5 0.096 20 0.01M 9.6 89% (96 h) 86%2 1.5 5 10 2100 0.08M 125 30% (96 h) 81% 3 1.5 5 10 2100 0.16M 62.5 41%(96 h) 79% 4 1.5 5 2.4 500 0.04M 60 20% (24 h) 81% 5 5 5 2.4 (p)^(a) 5000.04M 60 75% (40 h) 85% 6 5 5 2.4 (p)^(a) 500 0.08M 30 80% (20 h) 83% 75 5 2.4 (p)^(a) 500 0.16M 15 83% (20 h) 80% 8 5 5 2.4 (p)^(a) 500 0.32M7.5 92% (19 h) 74% 9 3 3 2.4 (p)^(a) 500 0.16M 15 57% (17 h) 80% 10 3 31.7 (p)^(a) 500 0.32M 5.3 75% (17 h) 74% ^(a)(p) refers to alkene 3 over98% pure.

Procedure E:

In a round bottomed flask, fitted with a magnetic stirrer weresequentially added alkene 3 (25 g, 119 mmol) and toluene (750 ml), thencatalyst B (3.6 g, 0.05 equiv, 5 mol %) and nitromethane (36.3 g, 595mmol, 5 equiv). The temperature was made 0° C. using an ice water bath,then K₂CO₃ (82 g, 595 mmol, 5 equiv) was added in one portion. Thereaction was stirred at 0-3° C. for 30 hours, then quenched water (250mL), the organic layer separated and the aqueous treated with dilutedHCl to pH ˜3; the aqueous layer was extracted with toluene (2×50 mL);the organic layer were combined, evaporated and the residue passedthrough a plug of silica eluting with DCM. The product was obtained in93% yield (30 g) as a sticky liquid and in 80% ee. Compound 5: Colorlesssolid, mp=43° C. (isopropanol Hexane 1:1); R_(f)=0.2 (PetroleumEther/Ethyl Acetate, 90:10); □_(H) (400 MHz, CDCl₃) 4.38 (2H, d, J=6),3.35 (1H, dd, J=15, J=6), 3.28 (1H, dd, J=15, J=7), 2.87 (1H, sept,J=7), 2.56 (3H, s), 1.68 (1H, sept, J=7), 1.36-1.23 (2H, m), 0.92 (3H,d, J=4), 0.90 (3H, d, J=4), □_(c) (100.6 MHz, CDCl₃) 172.1, 122.9, 78.5,40.9, 33.9, 30.0, 25.1, 22.4, 22.3, 11.7. HRMS: m/z found[M+H]⁺272.1212, C₁₁H₁₈N₃O₅ requires 272.1246.

Procedure F:

In a round bottomed flask, fitted with an overhead stirrer were chargedtoluene (330 mL) and K₂CO₃ (75.9 g, 550 mmol, 2.5 equiv). A solution ofalkene 3 (46.2 g, 220 mmol), nitromethane (26.8 g, 440 mmol, 2 equiv)and catalyst B (5.33 g, 0.04 equiv, 4 mol %) in toluene (110 mL) wascharged in a dropping funnel and added drop wise over a 2 h period. Thereaction was stirred at room temperature (21° C.) for 28 h, thenquenched with water (500 mL) and the organic layer separated. Theaqueous layer was treated with HCl conc to pH ˜3; the aqueous layer wasextracted with toluene (2×100 mL); the organic layer were combined,evaporated and the residue passed through a plug of silica eluting withDCM. The product was obtained in 92% yield (54.8 g) as a sticky liquidand in 68% ee.

NOTE 1: the reaction may have a induction period depending on purity ofalkene 3.NOTE 2: the reaction carried out by adding the solution ofalkene/nitromethane/catalyst over a period of 16 hours gave only 16%conversion in the same time.

Procedure G (Preparation of Racemic Compound 5):

In a round bottomed flask, fitted with an overhead stirrer were chargedtoluene (330 mL) and K₂CO₃ (75.9 g, 550 mmol, 2.5 equiv). A solution ofalkene 3 (46.2 g, 220 mmol), nitromethane (26.8 g, 440 mmol, 2 equiv)and N-tetrabutyl ammonium bromide (2.82 g, 0.04 equiv, 4 mol %) intoluene (110 mL) was charged in a dropping funnel and added drop wiseover a 2 h period. The reaction was stirred at room temperature (21° C.)for 28 h, then quenched with water (500 mL) and the organic layerseparated. The aqueous layer was treated with HCl conc to pH ˜3; theaqueous layer was extracted with toluene (2×100 mL); the organic layerwere combined, evaporated and the residue passed through a plug ofsilica eluting with DCM. The product was obtained in 94% yield (56 g) asa sticky liquid.

Alternative preparation of3-methyl-5-(4-methyl-2-nitromethyl-pentyl)-4-nitro-isoxazole (5)

TABLE 11 entry B (equiv) Solvent Base Catalyst Conv. A Yield % C 1 1.52.25 mL K₂CO₃ NEt₃ (1 equiv) 100 80 2 5 2.25 mL K₂CO₃ (5 equiv) I (0.1equiv) 100 70 (5% e.e.) 3 5 2.25 mL K₂CO₃ (5 equiv) II (0.1 equiv) 10020 (7% e.e.)

4-Methyl-1-nitro-pent-1-ene

(Alkene A) was prepared via condensation of isovaleraldehyde andnitromethane in presence of base according to a literature procedure[Liu, J-m; Wang, X.; Ge, Z-m; Sun, Q.; Cheng, T-m, Li, R-t Tetrahedron,2011, 67, 636].

Procedure:

To a solution of 4-methyl-1-nitro-pent-1-ene A (0.5 mmol) indichloromethane (2.25 mL) were sequentially added3,5-dimethyl-4-nitroisoxazole (5 equiv), catalyst and base as indicatedin table 11. The resulting mixture was then stirred at room temperaturefor 16 h, then quenched with sat ammonium chloride (3 mL). The organiclayer was separated, the solvent evaporated and the crude materialpurified via flash chromatography to give desired3-methyl-5-(4-methyl-2-nitromethyl-pentyl)-4-nitro-isoxazole 5.

Preparation of the Catalysts

N-benzyl-quinidinium bromide (4a):

To a suspension of quinidine (650 mg, 2.0 mmol, 1.0 eq.) in THF (12.0mL) benzyl bromide (0.31 mL, 2.6 mmol, 1.3 eq.) was added. The resultingmixture was heated at 60° C. for 16 h. The reaction was diluted withCH₂Cl₂ (10 mL) and washed with H₂O (3×15 mL). The organic phase wasdried over Na₂SO₄ and the solvent evaporated under reduced pressure. Thecrude material was purified by column chromatography(chloroform/methanol 95:5) affording the title compound as a purplesolid (512 mg, 52% yield). δ_(H) (400 MHz, CDCl₃): 8.60 (d, J=4.4, 1H),7.95 (d, J=9.2, 1H), 7.81 (d, J=4.4, 1H), 7.72-7.70 (m, 2H), 7.36 (d,J=2.8, 1H), 7.35-7.18 (m, 4H), 6.73-6.71 (m, 1H), 6.57-6.56 (m, 1H),6.02-5.89 (m, 2H), 5.25-5.19 (m, 3H), 4.67-4.55 (m, 1H), 3.95-3.90 (m,2H), 3.85 (s, 3H), 3.44-3.41 (m, 1H), 2.98-2.95 (m, 1H), 2.45-2.35 (m,2H), 1.90-1.80 (m, 3H), 1.09-1.01 (m, 1H); m.p.: 198-202° C.

N-(4,5-dimethoxybenzyl-2-nitrobenzyl)quinidinium bromide (4b)

To a suspension of quinidine (650 mg, 2.0 mmol, 1.0 eq.) in THF (12.0mL) 1-bromomethyl-4,5-dimethoxy-2-nitro-benzene (0.31 mL, 2.6 mmol, 1.3eq.) was added. The resulting mixture was heated at 60° C. for 16 h. Thereaction was diluted with CH₂Cl₂ (10 mL) and washed with H₂O (3×15 mL).The organic phase was dried over Na₂SO₄ and the solvent evaporated underreduced pressure. The crude material was purified by columnchromatography (chloroform/methanol 95:5) affording the title compoundas a purple solid (650 mg, 90% yield). δ_(H) (400 MHz, CDCl₃): 8.80 (m,1H), 8.30 (m, 1H), 8.10 (d, J=9.2, 1H), 7.90 (d, J=4.4, 1H), 7.72-7.70(m, 2H), 7.10 (m 1H), 6.93-6.71 (m, 3H), 6.57-6.56 (m, 1H), 6.80-5.73(m, 1H), 5.25-5.19 (m, 2H), 4.95-4.90 (m, 1H), 3.95 (s, 3H), 3.90 (s,3H), 3.85 (s, 3H), 3.44-3.41 (m, 1H), 2.98-2.95 (m, 1H), 2.45-2.35 (m,2H), 1.90-1.80 (m, 3H), 1.09-1.01 (m, 1H); m.p.: 202-205° C.

N-benzyl-cinchonidinium Bromide:

To a flame-dried flask equipped with a magnetic stirring bar and areflux condenser was added cinchonine (1.00 g, 3.4 mmol), THF (50 mL),and desired benzyl bromide derivative (3.4 mmol). The mixture was heatedto reflux until judged to be complete by TLC-analysis (CH₂Cl₂/MeOH 9:1)and then cooled to room temperature and poured onto Et₂O (150 mL) withstirring. The resulting suspension was stirred for 1 h and theprecipitated solids were isolated by filtration, which wasrecrystallized from MeOH/Et₂O as follows: to the crude product was added5-10 mL MeOH until the solid just dissolves at reflux and then themixture was placed at room temperature. To the warmed solution wasquickly added Et₂O until crystal formation was initiated and then thesolution was allowed to cool slowly to room temperature over night.Removal of the mother liquid and washing with Et₂O afforded the productas crystal. Prepared according to the general procedure, cinchonine(1.00 g, 3.4 mmol) and benzyl bromide (0.58 g, 3.4 mmol) gave theproduct as colourless crystals 1.37 g (reaction time 4.5 h). Isolatedyield 86.9% after recrystallisation. mp 259-261° C. (dec.); ¹H NMR (400MHz, CDCl₃) δ 8.84 (1H, d, J=5), 8.34 (1H, d, J=8), 7.93 (1H, d, J=4),7.64 (1H, d, J=8), 7.58 (2H, d, J=7.0), 7.22-6.98 (5H, m), 6.83-6.70(1H, m), 6.50 (1H, bs), 6.18-6.03 (1H, m), 5.89-5.76 (1H, m), 5.41-5.26(1H, m), 5.26-5.11 (2H, m), 4.49-4.38 (1H, m), 4.20-4.02 (2H, m), 3.29(1H, t, J=12 Hz), 2.74 (1H, dd, J=21, J=10), 2.27 (1H, dd, J=17, J=9Hz), 2.13-2.01 (1H, m), 1.82-1.63 (3H, m), 0.77-0.63 (1H, m); ¹³C NMR(100 MHz, CDCl₃) δ 149.1, 146.6, 144.9, 135.2, 134.0, 129.9, 129.2,128.6, 128.25, 127.3, 126.9, 123.5, 123.3, 119.7, 118.1, 66.7, 65.761.4, 56.3, 53.6, 53.4, 38.0, 27.2, 23.8, 21.8.

N-(3,5-bis(trifluoromethyl)benzyl) cinchonidinium bromide:

To a stirred suspension of cinchonidine (294.4 mg, 1.0 mmol) in toluene(4.0 mL), 3,5-bis(trifluoromethyl)benzyl bromide (220 μL, 1.2 mmol) wasadded. The resulting mixture was then heated at 80° C., and stirred for24 h at the same temperature. After cooling to r.t., the precipitate wascollected by Bückner filtration and washed several times with Et₂O,affording the title compound as a white solid in 75% yield. [α]D20=-126(c=0.81 in CH₃OH); 1H NMR (CD₃OD, 400 MHz) δ 8.94 (d, J=4.6 Hz, 1H),8.46 (s, 2H), 8.36-8.32 (m, 1H), 8.23 (s, 1H), 8.14-8.10 (m, 1H), 7.95(d, J=4.5 Hz, 1H), 7.88-7.89 (m, 2H), 6.66 (d, J=1.6 Hz, 1H), 5.68 (ddd,J=17.3, 10.5, 6.8 Hz, 1H), 5.41 (d, J=12.7 Hz, 1H), 5.31 (d, J=12.7 Hz,1H), 5.17 (dt, Jd=17.2 Hz, Jt=1.0 Hz, 1H), 4.99 (dt, Jd=10.5 Hz, Jt=1.1Hz, 1H), 4.58 (tddd, Jt=11.3 Hz, Jt=8.3, 5.1, 3.0 Hz, 1H), 4.05 (dd,J=9.7, 8.8 Hz, 1H), 3.80 (dddd, J=12.4, 7.9, 4.7, 3.3 Hz, 1H), 3.46 (dd,J=12.3, 10.6 Hz 1H), 3.38 (dt, Jt=11.4 Hz, Jd=4.8 Hz, 1H), 2.73 (bs,1H), 2.37-2.19 (m, 1H), 2.08 (bs, 1H), 1.96-1.84 (m, 1H), 1.48-1.37 (m,1H), 0.83-0.73 (m, 1H); 13C NMR (CD₃OD, 100 MHz) δ 149.9, 147.6, 146.1,137.3, 134.3 (q, J=4 Hz), 132.5 (q, J=36 Hz), 130.9, 130.0, 129.2,128.7, 128.1, 128.0, 125.1, 124.9, 123.3 (q, J=275 Hz), 123.0, 120.1,116.5, 69.1, 65.1, 62.2, 60.7, 51.8, 37.9, 26.7, 24.7, 21.3; 19F NMR(CD₃OD, 156 MHz) δ−64.6; ESI-MS: 521 [M+].

General Procedure for the Preparation of Catalysts A-E

In a round bottomed flask fitted with a magnetic stirrer and a refluxcondenser were put sequentially quinidine (1.0 equiv), the appropriatebenzyl bromide (1.05 equiv) and acetone to make a 0.18-0.20M solution.It was noted that at 50-55° C. the reaction became clear. The resultingsolution was heated at 60-65° C. for 2 h. The reaction mixture was thenallowed to reach room temperature, the solvent evaporated to give asolid which was suspended in petroleum ether, stirred for 30 minutes,then filtered and dried to give pure quinidinium bromides A-E.Optionally compounds A-B may be dissolved in the minimum quantity of DCMand then precipitated by addition of Et₂O.

NOTE 1: Commercial sources of quinidine always contain variable amountsof dihydroquinidine. This implies that Catalysts A-B and D-E may containvariable amounts of the corresponding dihydroquinidinium salt.NOTE 2: In the synthesis of compounds C-E, it was noted the formation ofa precipitate from hot acetone, minutes from refluxing at 60-65° C.NOTE 3: Compounds A-B may form sticky viscous oils when wet (Acetone,DCM); Drying under reduce pressure (rotavapor) gave compounds A-E as afine powder.

Catalyst A: N-(3,5-ditrifluoromethylbenzyl)quinidinium bromide:

light yellow powder; δ_(H) (400 MHz, CDCl₃) 8.39-8.36 (1H, m), 8.25-8.24(2H, m), 7.74 (1H, s), 7.67 (1H, d, J=8 Hz), 7.61 (1H, d, J=4 Hz), 7.49(1H, d, J=4 Hz), 6.95-6.92 (1H, m), 6.48-6.47 (1H, m), 6.12-6.09 (1H,m), 6.10 (1H, d, J=8 Hz), 5.82 (1H, d, J=8 Hz), 5.80-5.74 (1H, m),5.16-5.10 (2H, m), 4.56-4.50 (1H, m), 4.34-4.29 (1H, m), 4.15-4.10 (1H,m), 3.68 (3H, s), 3.08-3.02 (1H, m), 2.64-2.59 (1H, m), 2.39-2.19 (2H,m), 1.77-1.73 91H, m), 0.85-0.82 (1H, m); δ_(c) (100.6 MHz, CDCl₃)157.9, 147.0, 144.0, 142.0, 134.9, 133.9, 132.6, 132.3, 131.6, 130.4,126.0, 123.9, 121.2, 120.4, 120.0, 118.5, 103.2, 68.1, 67.1, 60.4, 60.2,56.5, 56.3, 54.5, 37.9, 27.0, 23.8, 21.9.

Catalyst B: N-(3,5-ditertbutylbenzyl)quinidinium bromide:

colourless powder; δ_(H) (400 MHz, CDCl₃) 8.61-8.59 (1H, m), 7.97-7.94(1H, m), 7.68-7.67 (1H, m), 7.60-7.59 (1H, m), 7.53-7.51 (1H, m),7.3-7.26 (2H, m), 6.79-6.77 (1H, m), 6.58-6.55 (1H, m), 6.00-5.92 (1H,m), 5.83-5.80 (1H, m), 5.19-5.15 (2H, m), 4.85-4.76 (1H, m), 4.62-4.57(1H, m), 4.10-4.04 (1H, m), 3.93 (3H, s), 3.88-3.83 (1H, m), 3.50-3.44(1H, m), 3.07-3.02 (1H, m), 1.89-1.85 (1H, m), 1.80-1.75 (1H, m),1.08-1.01 (1H, m);); δ_(c) (100.6 MHz, CDCl₃) 157.9, 152.0, 147.4,144.2, 143.0, 135.8, 131.8, 128.3, 126.2, 126.1, 124.4, 121.0, 120.5,118.1, 102.2, 68.4, 65.3, 64.3, 56.8, 56.0, 54.2, 38.3, 35.0, 31.4,30.9, 27.8, 24.2, 21.5.

Catalyst C: N-(3,5-ditertbutylbenzyl)dihydroquinidinium bromide:

colourless powder; δ_(H) (400 MHz, CDCl₃) 8.69-8.68 (1H, m), 8.03-8.00(1H, m), 7.75-7.74 (1H, m), 7.59-7.58 (2H, m), 7.54-7.53 (1H, m),7.63-7.29 (2H, m), 6.82-6.80 (1H, m), 6.66-6.62 (1H, m), 4.76-4.73 (1H,m), 4.42-4.36 (1H, m), 3.94 (3H, s), 3.74-3.65 (2H, m) 3.55-3.46 (1H,m), 3.14-3.06 (1H, m), 2.54-2.48 (1H, m), 1.94-1.88 (1H, m), 1.81-1.77(1H, m), 1.69-1.55 (3H, m), 0.88-0.84 (1H, m);); δ_(c) (100.6 MHz,CDCl₃) 158.0, 152.1, 147.7, 144.3, 143.1, 132.2, 128.3, 126.2, 126.0,124.5, 120.6, 120.5, 102.3, 68.9, 64.9, 64.6, 57.1, 56.0, 55.9, 36.2,35.0, 31.4, 31.3, 24.9, 24.6, 24.3, 21.3, 11.4.

Catalyst D: N-(3,5-dimethylbenzyl)quinidinium bromide:

colourless powder; δ_(H) (400 MHz, CDCl₃) 8.45-8.43 (1H, m), 7.89-7.86(1H, m), 7.71-7.70 (1H, m), 7.20-7.19 (1H, m), 7.20-7.17 (2H, m),6.89-6.88 (1H, m), 6.69-6.67 (1H, m), 6.47-6.45 (1H, m), 5.89-5.81 (1H,m), 5.73-5.69 (1H, m), 5.17-5.12 (2H, m), 4.53-4.48 (1H, m), 3.91-3.86(1H, m), 3.80 (3H, s), 3.43-3.38 (1H, m), 2.93-2.90 (1H, m), 2.39-2.3492H, m), 2.30 (6H, s), 1.80-1.65 (4H, m), 0.93-0.80 (1H, m); □_(c) (1 δ0.6 MHz, CDCl₃) 157.8, 147.3, 144.3, 142.6, 138.7, 135.6, 131.9, 131.7,131.4, 126.8, 126.4, 120.7, 120.6, 118.0, 102.8, 68.0, 66.9, 62.9, 56.6,56.0, 54.0, 38.2, 27.2, 24.0, 21.7, 21.3.

Catalyst E: N-(3,5-dibromobenzyl)quinidinium bromide:

colourless powder; δ_(H) (400 MHz, CDCl₃) 8.36-8.35 (1H, m), 7.82-7.74(4H, m), 7.66-7.65 (1H, m), 7.04-7.01 (1H, m), 6.58-6.56 (1H, m),6.44-6.40 (1H, m), 6.17-6.15 (1H, m), 5.86-5.79 (1H, m), 5.64-5.59 (1H,m), 5.28-5.22 (2H, m), 4.55-4.52 (1H, m), 4.27-4.25 (2H, m), 3.70 (3H,s), 3.23-3.20 (1H, m), 2.79-2.76 (1H, m), 2.40-2.38 (1H, m), 2.25-2.21(1H, m), 1.85-1.77 (3H, m), 0.93-0.85 (1H, m);); δ_(c) (100.6 MHz,CDCl₃)157.7, 147.0, 144.1, 142.0, 136.2, 135.1, 135.0, 131.6, 131.1,126.3, 123.5, 120.5, 119.5, 118.2, 103.8, 67.7, 59.8, 56.3, 56.0, 54.2,37.9, 27.0, 23.8, 22.0, 15.3.

Preparation of 5-Methyl-3-nitromethyl-hexanoic acid (6) (Procedure A):

A solution of adduct 5, (0.25 mmol) in THF (0.5 mL) was charged in around bottomed flask and treated with an aqueous solution of NaOH (1N,1.35 mL, 5.5 equiv.). The resulting deep yellow solution was refluxed (Tof the oil bath=100° C.) for 1 h, then allowed to reach roomtemperature, the THF evaporated in vacuo and the aqueous solution soobtained was made acidic (pH=2) by addition of 6N aqueous HCl. Theaqueous solution obtained was evaporated in vacuo to give a solid whichwas then washed with DCM (2×10 mL). Compound 6 was obtained as solid in70% yield upon evaporation of the DCM solution. ¹H NMR (400 MHz, CDCl₃)δH 4.50 (1H, dd, J=12, J=7), 4.44 1H, dd, J=12, J=6) 2.67 (1H, sep J=6Hz), 2.49 (2H, d, J=6), 1.66 (1H, sept, J=7), 1.28 (2H, m), 0.93 (3H, d,J=7), 0.91 (3H, d, J=7). ¹³C NMR δ_(c)(100.1 MHz, CDCl₃) 177.6, 78.4,40.3, 35.6, 31.7, 24.9, 22.3, 22.0.

Preparation of 5-Methyl-3-nitromethyl-hexanoic acid (6) (Procedure B):

To a solution of adduct 5, (0.25 mmol) in THF (0.5 mL) was addeddropwise a solution of KMnO₄ (3 equiv) in H₂O:Acetone (4:1) 4.5 mL. Thereaction mixture was stirred for 1 hour at room temperature and then aNa₂SO₃ saturated solution (5 mL) was added to destroy the excess ofKMnO₄: the formation of a brown precipitate was observed (MnO₂). Themixture was then acidified with HCl 6 M until pH=3. At this point it wasnoted that the solution became clear. The mixture was then extractedwith DCM (3×1 mL) and the combined organic phases were evaporated.Compound 6 was obtained as solid in 90% yield upon evaporation of theDCM solution.

Preparation of 5-Methyl-3-nitromethyl-hexanoic acid (6) (Procedure C):

A solution of adduct 5, (39.2 g 144 mmol) in THF (100 mL) was charged ina round bottomed flask and treated with a freshly made aqueous solution(1N, 720 mL, 5 equiv.) of NaOH (28.8 g, 720 mmol). The resulting darksolution was refluxed (T=60-65° C.) for 16 h, then allowed to reach roomtemperature, the THF evaporated in vacuo and the aqueous solution soobtained was extracted with toluene (300 mL). the aqueous layer was madecold (0° C.) by an ice water bath, then HCl conc was added drop wisewith stirring until pH ˜2-3. This addition must be done carefully toavoid formation of side products. The aqueous solution was thenextracted with toluene (3×200 mL), the organic layer washed with water(2×150 mL) and concentrated in vacuo to give acid 6 as a yellow brownviscous oil (25.2, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.50 (1H,dd, J=12, J=7), 4.44 1H, dd, J=12, J=6) 2.67 (1H, sep J=6 Hz), 2.49 (2H,d, J=6), 1.66 (1H, sept, J=7), 1.28 (2H, m), 0.93 (3H, d, J=7), 0.91(3H, d, J=7). ¹³C NMR δ_(c)(100.1 MHz, CDCl₃) 177.6, 78.4, 40.3, 35.6,31.7, 24.9, 22.3, 22.0.

NOTE 1: starting from adduct 5 68% ee enantioenriched, compound 6 wasobtained in 68% ee; starting from adduct 5 85% ee enantioenriched,compound 6 was obtained in 85% ee.

Preparation of (S)-Pregabalin (7):

Compound 6 was reduced to 7 using a literature procedure described in F.Felluga, G. Pitacco, E. Valentin, C. D. Venneri Tetrahedron: Asymm.2008, 945 which is incorporated herein by reference.

Preparation of (S)-Pregabalin (7)-Reduction of Compound 6 using Pd/C:

In a round bottomed flask were charged compound 6 (50 g, 264 mmol,Mw=189, 80% ee), methanol (260 mL) and Pd/C (10%, 15 g). The suspensionobtained was stirred at room temperature for 24 h under an atmosphere ofH₂ (1 atm) then filtered through a pad of celite and the solutionevaporated to give a white solid which was washed with hexane (20 mL) togive (S)-pregabalin (40.3 g, 96% yield).

NOTE 1: the reduction could be carried out under pressure at roomtemperature (18° C.).

Preparation of (S)-Pregabalin (7)-Reduction of Compound 6 Using Ni/Ra:

In a round bottomed flask were charged compound 6 (50 g, 264 mmol,Mw=189, 80% ee), methanol (250 mL) and Ni Raney (10%, 5 g). Thesuspension obtained was stirred at room temperature under an atmosphereof H₂ (10 atm) for 16 h, then filtered through a pad of celite and thesolution evaporated to give (S)-pregabalin (39.4 g, 94% yield) as acolourless solid.

Preparation of (S)-Pregabalin (7)-Crystallisation of enantiopure(S)-Pregabalin:

Enantioenriched (S)-pregabalin (30 g, 68-86% ee) was dissolved in hotisopropanol (100 mL), then water (35 mL) added and the mixture allowedto reach room temperature (18° C.) and then cooled at 0° C., to give aprecipitate of (S)-pregabalin (60% to 80% yield).

Preparation of (S)-Pregabalin (7)-Partial resolution of (S)-Pregabalin:

To a solution of enantioenriched (S)-pregabalin (30 g, 68-86% ee) in hotisopropanol (120 mL) water (25 mL) was added (R)-(−)-mandelic acid(0.2-0.1 equiv) and the solution refluxed for 30 minutes, then allowedto reach room temperature (18° C.) and finally cooled at 0° C., to givea precipitate of (R)-pregabalin/(R)-(−)-mandelic acid. The filtrate wasconcentrated to give enantiopure (S)-pregabalin in 84-92% yield.

Analogues of compound 8 were prepared using a similar method to thatabove and are exemplified below.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-propan-2-ol (9)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.38-4.33 (1H, m), 3.37 (1H, dd, J=15 J=7), 3.35(1H, dd, J=15 J=4), 2.56 (3H, s), 1.35 (3H, d, J=6); δ_(c) (100.6 MHz,CDCl₃) 172.6, 155.8, 66.1, 37.1, 23.8, 11.8. HRMS: m/z found[M+H]⁺187.0742, C₇H₁₁N₂O₄ requires 187.0719.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-butan-2-ol (10)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.09-4.06 (1H, m), 3.36 (1H, dd, J=15 J=4), 3.35(1H, dd, J=15 J=6), 2.56 (3H, s), 1.66-1.59 (2H, m), 1.03 (3H, t, J=7);δ_(c) (100.6 MHz, CDCl₃) 172.9, 155.8, 130.8, 71.1, 35.2, 30.6, 11.8,9.8. HRMS: m/z found [M+H]⁺201.0851, C₈H₁₃N₂O₄ requires 201.0875.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-pentan-2-ol (11)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.17-4.11 (1H, m), 3.36 (1H, dd, J=15 J=4), 3.32(1H, dd, J=15 J=6), 2.55 (3H, s), 1.60-1.38 (4H, m), 0.94 (3H, t, J=7);δ_(c) (100.6 MHz, CDCl₃) 172.9, 155.8, 130.8, 69.5, 39.8, 35.7, 18.8,13.9, 11.8. HRMS: m/z found [M+H]⁺215.1011, C₉H₁₅N₂O₄ requires 215.1032.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-hexan-2-ol (12)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.16-4.10 (1H, m), 3.38 (1H, dd, J=15 J=4), 3.33(1H, dd, J=15 J=6), 2.58 (3H, s), 1.62-1.21 (6H, m), 0.86 (3H, t, J=7);δ_(c) (100.6 MHz, CDCl₃) 172.9, 155.8, 69.9, 37.5, 35.7, 27.7, 22.6,21.2, 14.1, 11.8. HRMS: m/z found [M+H]⁺229.1196, C₁₀H₁₇N₂O₄ requires229.1188.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-nonan-2-ol (13)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.15-4.12 (1H, m), 3.38 (1H, dd, J=15 J=4), 3.33(1H, dd, J=15 J=6), 2.56 (3H, s), 1.60-1.57 (2H, m), 1.38-1.20 (10H, m),0.88 (3H, t, J=7); δ_(c) (100.6 MHz, CDCl₃) 172.9, 155.8, 130.8, 69.9,37.8, 35.7, 31.9, 29.8, 29.4, 25.5, 22.8, 14.2, 11.8. HRMS: m/z found[M+H]⁺271.1669, C₁₃H₂₃N₂O₄ requires 271.1658.

1-(3-Methyl-4-nitro-isoxazol-5-yl)-decan-2-ol (14)

Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.17-4.12 (1H, m), 3.38 (1H, dd, J=15 J=4), 3.33(1H, dd, J=15 J=6), 2.56 (3H, s), 1.62-1.56 (2H, m), 1.38-1.20 (12H, m),0.88 (3H, t, J=7); δ_(c) (100.6 MHz, CDCl₃) 172.9, 155.8, 130.9, 69.9,37.8, 35.7, 31.9, 29.6, 29.5, 29.3, 25.5, 22.8, 14.2, 11.8. HRMS: m/zfound [M+H]⁺285.1828, C₁₄H₂₅N₂O₄ requires 285.1814.

Analogues of compound 3 were prepared using a similar method to thatabove and are exemplified below.

3-Methyl-4-nitro-5-propenyl-isoxazole (15)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.10-7.06 (2H, m), 2.55 (3H, s), 2.08-2.06 (3H,m); δ_(c) (100.6 MHz, CDCl₃) 167.1, 156.0, 144.0, 116.1, 19.7, 12.0.HRMS: m/z found [M]⁺168.0554, C₇H₈N₂O₃ requires 168.0535.

5-But-1-enyl-3-methyl-4-nitro-isoxazole (16)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.18-7.01 (2H, m), 2.56 (3H, s), 2.44-2.38 (2H,m), 1.17 (3H, t, J=7), δ_(c) (100.6 MHz, CDCl₃) 167.3, 156.0, 150.2,113.8, 29.8, 26.9, 11.9. HRMS: m/z found [M]⁺182.0648, C₈H₁₀N₂O₃requires 182.0691.

3-Methyl-4-nitro-5-pent-1-enyl-isoxazole (17)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.11-7.00 (2H, m), 2.54 (3H, s), 2.38-2.33 (2H,m), 1.62-1.53 (2H, m), 0.98 (3H, t, J=7); δ_(c) (100.6 MHz, CDCl₃)167.1, 156.0, 148.8, 114.7, 35.8, 21.6, 13.8, 11.9. HRMS: m/z found[M]⁺196.0856, C₉H₁₂N₂O₃ requires 196.0848.

5-Hex-1-enyl-3-methyl-4-nitro-isoxazole (18)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.12-7.00 (2H, m), 2.55 (3H, s), 2.41-2.35 (2H,m), 1.56-1.48 (2H, m), 1.43-1.38 (2H, m), 0.94 (3H, t, J=7); δ_(c)(100.6 MHz, CDCl₃) 167.2, 156.0, 149.0, 114.6, 33.5, 30.4, 22.4, 16.9,11.9. HRMS: m/z found [M]⁺210.1016, C₁₀H₁₄N₂O₃ requires 210.1004.

3-Methyl-4-nitro-5-non-1-enyl-isoxazole (19)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.13-6.95 (2H, m), 2.56 (3H, s), 2.40-2.35 (2H,m), 1.56-1.50 (2H, m), 1.37-1.25 (8H, m), 0.87 (3H, t, J=7); δ_(c)(100.6 MHz, CDCl₃) 167.2, 156.0, 149.2, 114.6, 33.9, 31.9, 29.8, 29.3,29.2, 28.3, 22.8, 14.2, 12.0. HRMS: m/z found [M]⁺252.1448, C₁₃H₂₀N₂O₃requires 252.1474.

5 Dec-1-enyl-3-methyl-4-nitro-isoxazole (20)

Colorless liquid; R_(f)=0.8 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 7.13-6.95 (2H, m), 2.57 (3H, s), 2.45-2.38 (2H,m), 1.65-1.20 (12H, m), 0.89 (3H, t, J=7), δ_(c) (100.6 MHz, CDCl₃)167.2, 156.0, 149.2, 114.6, 33.9, 31.9, 29.5, 29.3, 28.3, 22.8, 14.2,11.9. HRMS: m/z found [M]⁺266.1630, C₁₄H₂₂N₂O₃ requires 266.1630.

Analogues of compound 5 were prepared using a similar method to thatabove and are exemplified below.

3-Methyl-5-(2-methyl-3-nitro-propyl)-4-nitro-isoxazole (21)

Compound 21: Procedure B, 91% yield, 93% ee Colorless liquid; R_(f)=0.2(Petroleum Ether/Ethyl Acetate, 90:10); δ_(H) (400 MHz, CDCl₃) 4.44 (1H,dd, J=12, J=6), 4.37 (1H, dd, J=12, J=6), 3.35 (1H, dd, J=15, J=7), 3.26(1H, dd, J=15, J=7), 2.96 (1H, sept, J=6), 2.59 (3H, s), 1.15 (3H, d,J=7); δ_(c) (100.6 MHz, CDCl₃) 172.2, 156.0, 78.1, 37.4, 29.8, 11.8,10.8. HRMS: m/z found [M+H]⁺230.0714, C₈H₁₂N₂O₅ requires 230.0777.

3-Methyl-4-nitro-5-(2-nitromethyl-butyl)-isoxazole (22)

Compound 22: Procedure B, 91% yield, 93% ee Colorless liquid; R_(f)=0.2(Petroleum Ether/Ethyl Acetate, 90:10); δ_(H) (400 MHz, CDCl₃) 4.47 (1H,dd, J=13, J=6), 4.42 (1H, dd, J=13, J=6), 3.38 (1H, dd, J=15, J=7), 3.28(1H, dd, J=15, J=7), 2.76 (1H, sept, J=6), 2.58 (3H, s), 1.32-1.27 (2H,m), 1.03 (3H, t, J=7); δ_(c) (100.6 MHz, CDCl₃) 172.2, 156.0, 78.1,37.4, 29.8, 24.7, 11.8, 10.8. HRMS: m/z found [M+H]⁺244.0968, C₉H₁₄N₂O₅requires 244.0933.

3-3-Methyl-4-nitro-5-(2-nitromethyl-pentyl)-isoxazole (23)

Compound 23: Procedure A 92% yield, 84% ee; Procedure B, 91% yield, 92%ee Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.45 (1H, dd, J=12, J=6), 4.40 (1H, dd, J=12,J=6), 3.37 (1H, dd, J=15, J=7), 3.30 (1H, dd, J=15, J=7), 2.82 (1H,sept, J=6), 2.58 (3H, s), 1.46-1.40 (4H, m), 0.94 (3H, t, J=7); δ_(c)(100.6 MHz, CDCl₃) 172.2, 156.0, 78.4, 35.8, 29.8, 19.7, 13.7, 11.8.HRMS: m/z found [M+H]⁺258.1054, C₁₀H₁₆N₂O₅ requires 258.1090.

3-3-Methyl-4-nitro-5-(2-nitromethyl-pentyl)-isoxazole (24)

Compound 24: Procedure A 92% yield, 84% ee; Procedure B, 91% yield, 93%ee Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.43 (1H, dd, J=12, J=6), 4.40 (1H, dd, J=12,J=6), 3.37 (1H, dd, J=15, J=7), 3.30 (1H, dd, J=15, J=7), 2.81 (1H,sept, J=6), 2.58 (3H, s), 1.50-1.27 (4H, m), 0.88 (3H, t, J=7); δ_(c)(100.6 MHz, CDCl₃) 172.3, 156.0, 129.2, 78.4, 36.0, 31.4, 29.9, 28.5,22.6, 14.0, 11.8. HRMS: m/z found [M+H]⁺272.1280, C₁₁H₁₈N₃O₃ requires272.1246.

3-Methyl-4-nitro-5-(2-nitromethyl-nonyl)-isoxazole (25)

Compound 25: procedure A: 96% yield, 80% ee; procedure B, 91% yield, 91%ee. Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.45 (1H, dd, J=8, J=6), 4.40 (1H, dd, J=8, J=6),3.37 (1H, dd, J=15, J=7), 3.30 (1H, dd, J=15, J=7), 2.81 (1H, sept,J=6), 2.58 (3H, s), 1.50-1.27 (12H, m), 0.88 (3H, t, J=7); δ_(c) (100.6MHz, CDCl₃) 172.3, 156.0, 78.4, 36.0, 31.8, 31.7, 29.9, 29.4, 29.1,26.3, 22.7, 14.2, 11.8. HRMS: m/z found [M+H]⁺314.1745, C₁₄H₂₄N₃O₃requires 314.1716.

3-Methyl-4-nitro-5-(2-nitromethyl-decyl)-isoxazole (26)

Compound 26: procedure A: 96% yield, 84% ee; procedure B, 91% yield, 94%ee. Colorless liquid; R_(f)=0.2 (Petroleum Ether/Ethyl Acetate, 90:10);δ_(H) (400 MHz, CDCl₃) 4.45 (1H, dd, J=8, J=6), 4.40 (1H, dd, J=8, J=6),3.36 (1H, dd, J=15, J=7), 3.30 (1H, dd, J=15, J=7), 2.81 (1H, sept,J=6), 2.58 (3H, s), 1.48-1.26 (14H, m), 0.86 (3H, t, J=7); δ_(c) (100.6MHz, CDCl₃) 172.3, 156.0, 78.4, 36.0, 31.9, 31.7, 29.9, 29.8, 28.4,29.4, 26.3, 22.7, 14.2, 11.8. HRMS: m/z found [M+H]⁺328.1849, C₁₅H₂₆N₃O₅requires 328.1872.

1. A process for the preparation of a compound of formula (I), or apharmaceutically acceptable salt, solvate or prodrug thereof:

wherein: R¹ is selected from an alkyl group, an alkenyl group, analkynyl group and a cycloalkyl group, each of which may be optionallysubstituted; and * denotes a chiral centre; which process comprises thestep of reacting a compound of formula (IV) with nitromethane in thepresence of a catalyst to provide a compound of formula (V);

wherein R¹ and * are as defined above and R² is an alkyl group or arylgroup, each of which may be optionally substituted; and X is an electronwithdrawing group.
 2. (canceled)
 3. (canceled)
 4. (canceled) 5.(canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled) 10.(canceled)
 11. (canceled)
 12. (canceled)
 13. The process according toclaim 1 wherein the compound of formula (IV) is prepared by reacting acompound of formula (III) with a compound of formula (II):


14. (canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled) 18.(canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled)23. (canceled)
 24. (canceled)
 25. A process for the preparation of acompound of formula (I), or a pharmaceutically acceptable salt, solvateor prodrug thereof:

wherein: R¹ is selected from an alkyl group, an alkenyl group, analkynyl group and a cycloalkyl group, each of which may be optionallysubstituted; and * denotes a chiral centre; which process comprises thestep of preparing a compound of formula (IV) by reacting a compound offormula (III) with a compound of formula (II):

wherein R¹ and * are as defined above and R² is an alkyl group or arylgroup, each of which may be optionally substituted; and X is an electronwithdrawing group.
 26. (canceled)
 27. (canceled)
 28. A process for thepreparation of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or prodrug thereof:

wherein: R¹ is selected from an alkyl group, an alkenyl group, analkynyl group and a cycloalkyl group, each of which may be optionallysubstituted; and * denotes a chiral centre; which process comprisespreparing a compound of formula (IV) by reacting a compound of formula(IIIA) with a compound of formula (II) to form a compound of formula(IIIB):

wherein L is a hydroxyl activating group, R¹ is selected from an alkylgroup, an alkenyl group, an alkynyl group and a cycloalkyl group, eachof which may be optionally substituted, and R² is an alkyl group or arylgroup, each of which may be optionally substituted converting thecompound of formula (IIIB) to a compound of formula (IIIC):

wherein X is an electron withdrawing group; and converting the compoundof formula (IIIC) to a compound of formula (IV):


29. The process according to claim 28 which further comprises the stepof reacting the compound of formula (IV) with nitromethane in thepresence of a catalyst to form a compound of formula (V)


30. (canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled) 34.(canceled)
 35. (canceled)
 36. (canceled)
 37. The process accordingly toclaim 1 which further comprises the step of hydrolysing the compound offormula (V) to provide a compound of formula (VI)


38. (canceled)
 39. The process accordingly to claim 1 which furthercomprises the step of reducing the compound of formula (V) to provide acompound of formula (VIb)

with the proviso that X is not NO₂.
 40. (canceled)
 41. The processaccording to claim 37 which further comprises the step of reducing thecompound of formula (VI) to the compound of formula (I):


42. (canceled)
 43. The process according to claim 39 which furthercomprises the step of hydrolysing the compound of formula (VIb) toprovide a compound of formula (I)

with the proviso that X is not NO₂.
 44. (canceled)
 45. The processaccording to claim 1 wherein R¹ is an optionally substituted alkylgroup.
 46. The process according to claim 1 wherein R¹ and R² areindependently selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyland n-octyl.
 47. The process according to claim 46 wherein R¹ isiso-butyl and R² is methyl.
 48. The process according to claim 1 whereinX is a group selected from NO₂, CN, COOR³ and SO₂R³; wherein R³ is H oran optionally substituted alkyl group.
 49. The process according toclaim 48 wherein X is NO₂.
 50. (canceled)
 51. The process according toclaim 1 wherein the compound of formula (I) is isolated with anenantiomeric excess of greater than about 70%, preferably greater thanabout 80%, even more preferably greater than about 90%.
 52. (canceled)53. (canceled)
 54. (canceled)
 55. (canceled)
 56. (canceled) 57.(canceled)
 58. (canceled)
 59. (canceled)
 60. The process according toclaim 1 wherein the catalyst is a cinchona alkaloid derivative.
 61. Theprocess according to claim 1 wherein the catalyst is a compound offormula (VIIa) or (VIIb)

wherein, M is selected from H, hydroxy, alkoxy, O-alkenyl,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl, amino,NR¹¹C(═O)R¹², C(═O)NR¹³R¹⁴, C(═O)R¹², O(C═O)R¹², C(═O)OR¹², NR¹¹SO₂R¹²,and R⁷; in which each aryl, heteroaryl and cycloalkyl groups may beoptionally substituted; R⁴ is selected from hydroxy, alkoxy, O-alkenyl,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl, amino,NR¹¹C(═O)R¹², C(═O)NR¹³R¹⁴, C(═O)R¹², O(C═O)R¹², C(═O)OR¹², NR¹¹SO₂R¹²,and R⁷; in which each aryl, heteroaryl and cycloalkyl groups may beoptionally substituted; R¹¹, R¹², R¹³ and R¹⁴ are independently selectedfrom H, an alkyl group, an alkenyl group, an alkynyl group, an arylgroup, a heteroaryl group and a cycloalkyl group, each of which may beoptionally substituted; or R¹³ and R¹⁴ may together define an optionallysubstituted C₃-C₂₀ cycloalkyl group or C₅-C₁₅ heteroaryl group; R⁵ andR^(5a) are independently selected from H, alkyl and alkenyl, each ofwhich may be optionally substituted; R⁶ is selected from an alkyl group,an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, acycloalkyl group, a (CH₂)_(n)-aryl group, a (CH₂)_(n)-heteroaryl groupand a (CH₂)_(n)-cycloalkyl group; each of which may be optionallysubstituted; n=0 to 6; R⁷ is

wherein Q is O or S; and R⁸, R⁹ and R¹⁰ are independently selected fromH, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, aheteroaryl group and a cycloalkyl group, each of which may be optionallysubstituted, or R⁸ and R⁹ may together define an optionally substitutedC₃-C₂₀ cycloalkyl group or an optionally substituted C₅-C₁₅ heteroarylgroup; and Y⁻ is a counterion.
 62. The process according to claim 61wherein the catalyst is a compound of formula (VIIa) wherein: M isselected from H, hydroxy, alkoxy, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷; R⁴ is selected fromhydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl, C(═O)OR¹², amino,NR¹¹SO₂R¹², and R⁷; Q is S; R⁵ and R^(5a) are independently selectedfrom H, methyl, ethyl, propyl, ethenyl, propenyl; R⁸ is selected from analkyl group, an aryl group and a cycloalkyl group each of which may beoptionally substituted by one or more of halo, CF₃, Me and OMe; R⁹, R¹⁰,R¹¹ are independently selected from H and alkyl; and R¹² is selectedfrom H, alkyl, aryl and cycloalkyl; each of which may be optionallysubstituted by one or more of halo, CF₃, Me and OMe.
 63. The processaccording to claim 61 wherein the catalyst is a compound of formula(VIIb) wherein: M is selected from H, hydroxy, alkoxy, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-cycloalkyl and R⁷; R⁴ is selected fromhydroxy, alkoxy, O-alkenyl, O(CH₂)_(n)-aryl, C(═O)OR12, amino,NR¹¹SO₂R¹², and R⁷; Q is S; R⁵ and R^(5a) are independently selectedfrom H, methyl, ethyl, propyl, ethenyl, propenyl; R⁶ is selected from(CH₂)_(n)-aryl groups, (CH₂)_(n)-heteroaryl groups and(CH₂)_(n)-cycloalkyl groups, each of which may optionally be substitutedwith one or more halo, alkyl, NO₂, haloalkyl and methoxy groups; R⁸ isselected from an alkyl group, an aryl group and a cycloalkyl group eachof which may be optionally substituted by one or more of halo, CF₃, Meand OMe; R⁹, R¹⁰, R¹¹ are independently selected from H and alkyl; andR¹² is selected from H, alkyl, aryl and cycloalkyl; each of which may beoptionally substituted by one or more of halo, CF₃, Me and OMe.
 64. Theprocess according to claim 1 wherein the catalyst is selected from:

wherein Y⁻ is a counterion.
 65. The process according to claim 1 whereinthe catalyst is selected from N-(3,5-ditrifluoromethylbenzyl)quinidiniumbromide, N-(3,5-ditertbutylbenzyl)quinidinium bromide,N-(3,5-ditertbutylbenzyl)dihydroquinidinium bromide,N-(3,5-dimethylbenzyl)quinidinium bromide,N-(3,5-dibromobenzyl)quinidinium bromide, N-benzylcinchonidiniumbromide, N-(4,5-dimethoxy-2-nitrobenzyl)cinchonidinium bromide,N-(3,5-bis(trifluoromethyl)benzyl)cinchonidinium bromide,N-benzylquinidinium bromide, N-(2-nitro-4,5-dimethoxybenzyl)quinidiniumbromide.
 66. The process according to claim 1 wherein the step ofreacting a compound of formula (IV) with nitromethane in the presence ofa catalyst is carried out in the presence of a base.
 67. (canceled) 68.(canceled)
 69. (canceled)
 70. (canceled)
 71. (canceled)
 72. (canceled)73. (canceled)
 74. (canceled)
 75. (canceled)
 76. (canceled) 77.(canceled)
 78. (canceled)
 79. (canceled)
 80. (canceled)
 81. (canceled)82. (canceled)
 83. A process according to any one of claim 1 wherein thecatalyst is a chiral catalyst.